Vinylarene derivative and application

ABSTRACT

The present invention relates to a vinylarene deriv. which modulates or inhibits the enzymic activity of indoleamine 2,3-dioxygenase 1 (IDO-1), and the use thereof, and further relates to a vinylarene deriv. and the use thereof. The vinylarene deriv. and its stereoisomer, cis- or trans-isomer, or tautomer thereof and pharmaceutically acceptable salt thereof, has an IDO-1 enzyme inhibitory activity, and is expected to provide brand new therapeutic methods and schemes for related diseases caused by IDO enzymes.

FIELD OF THE INVENTION

The invention relates generally to compounds vinylarene derivative that modulate or inhibit the enzymatic activity of indoleamine 2,3-dioxygenase 1 (IDO-1) and its application, further vinylarene derivative and its application.

BACKGROUND OF THE INVENTION

Indole-2,3-dioxygenase (IDO) is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step in the degradation of amino acid L-tryptophan. IDO catalyzes the essential amino acids L-tryptophan to N-formyl kynurenine and cleans up L-tryptophan in humans. By degrading tryptophan, IDO causes a microenvironment in which tryptophan is absent in the body, which in turn leads to a variety of diseases related to tryptophan deficiency such as cancer, viral infection, depression, organ transplant rejection or autoimmune diseases. Therefore, in recent years, the research of high-efficiency IDO inhibitors has become a hot research in drug development.

There are no IDO-1 inhibitors were approved for listing, and the diseases associated with IDO-1 enzymes still lack treatment methods and treatment options. The development of IDO-1 enzyme inhibitors has a huge potential market.

SUMMARY OF THE INVENTION

The purpose of the invention is to provide a compound which modulates or inhibits the enzymatic activity of IDO and/or a pharmaceutically acceptable salt, its stereoisomer, cis-trans isomer and a tautomer, and a method which modulates or inhibits IDO-1 enzymatic activity, and a application of the compound for the preparation of pharmaceutical.

In order to achieve the above purposes, the technical scheme adopted by the present invention is as follows:

The present invention is a vinylarene derivative as a regulator or inhibitor of indoleamine-2,3-dioxygenase (IDO-1). The aromatic ethylene derivative is a compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof.

wherein

W is selected from CH₂, O or NH;

X is selected from CH₂, O or NH;

Y is selected from O or S:

J is selected from N or C;

K is selected from N or C;

M is selected from N or C;

R¹ and R² are selected from H, COOH, CONHR¹⁰, —CONHSO₂R¹⁰, COOR¹⁰, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl;

R³ is selected from H, C₁-C₁₂ alkyl, halo C₁-C₁₂ alkyl, C₂-C₂ alkenyl, halo C₂-C₁₂ alkenyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl;

R⁴ is selected from H or halogen;

R⁵ is selected from H or halogen;

R⁶ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ heterocycloalkyl, halo C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, halo C₁-C₁₂ alkoxy, C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, halo C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₃-C₁₂ cycloalkenyl, halo C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, halo C₂-C₁₂ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₁₂ alkyl, heteroaryl C₁-C₁₂ alkyl, aryl C₁-C₁₂ alkoxy, heteroaryl C₁-C₁₂ alkoxy, aryloxy or heteroaryloxy;

R⁷ and R⁸ are the same or different and selected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ heterocycloalkyl, halo C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, halo C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₃-C₁₂ cycloalkenyl, halo C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, halo C₂-C₁₂ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₁₂ alkyl, heteroaryl C₁-C₁₂ alkyl;

R⁹ is selected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ heterocycloalkyl, halo C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, halo C₁-C₁₂ alkoxy, C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, halo C₂-C₁₂ alkoxy C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₃-C₁₂ cycloalkenyl, halo C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, halo C₂-C₁₂ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₁₂ alkyl, heteroaryl C₁-C₁₂ alkyl;

R¹⁰ is selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, halo C₁-C₁₂ alkyl, halo C₃-C₁₂ cycloalkyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₁₂ alkyl, heteroaryl C₁-C₁₂ alkyl;

R¹¹ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₁₀ alkyl, halo C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthiol, C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkoxycarbonyl, C₂-C₁₀ alkenyl, halo C₂-C₁₀ alkenyl, C₃-C₁₀ alkenyloxy, halo C₃-C₁₀ alkenyloxy, C₂-C₁₀ alkynyl, halo C₂-C₁₀ alkynyl, C₃-C₁₀ alkynyloxy, halo C₃-C₁₀ alkynyloxy, halo C₁-C₁₀ alkylthiol, halo C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkylamino, halo C₁-C₁₀ alkylamino, C₂-C₁₀ dialkylamino, C₁-C₁₀ alkylcarbonylamino, halo C₁-C₁₀ alkylcarbonylamino, C₁-C₁₀ alkylaminocarbonyl or halo C₁-C₁₀ alkylaminocarbonyl.

The compound of the formula I, its stereoisomers, cis-trans isomers, tautomers and pharmaceutically acceptable salts thereof, the more preferred compounds of the formula are:

W is selected from CH₂, O or NH;

X is selected from CH₂, O or NH;

Y is selected from O or S;

J is selected from N or C;

K is selected from N or C;

M is selected from N or C:

R¹ and R² are selected from the group consisting of COOH, CONHR¹⁰, —CONHSO₂R¹⁰, COOR¹⁰, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl;

R³ is selected from the group consisting of H, C₁-C₆ alkyl, halo C₁-C₆ alkyl, C₂-C₆ alkenyl, halo C₂-C₆ alkenyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl;

R⁴ is selected from H or halogen;

R⁵ is selected from H or halogen;

R⁶ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₆ alkyl, heteroaryl C₁-C₆ alkyl, aryl C₁-C₆ alkoxy, heteroaryl C₂-C₆ alkoxy, aryloxy or heteroaryloxy;

R⁷ and R⁸ are the same or different and selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₆ alkyl, heteroaryl C₁-C₆ alkyl;

R⁹ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl;

R¹⁰ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo C₁-C₆ alkyl, halo C₃-C₆ cycloalkyl, unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₆ alkyl, heteroaryl C₁-C₆ alkyl;

R¹¹ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₆ alkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkylthiol, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₂-C₆ alkenyl, halo C₂-C₆ alkenyl, C₃-C₆ alkenyloxy, halo C₃-C₆ alkenyloxy, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, C₃-C₆ alkynyloxy, halo C₃-C₆ alkynyloxy, halo C₁-C₆ alkylthiol, halo C₁-C₆ alkylcarbonyl, C₁-C₆ alkylamino, halo C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₁-C₆ alkylcarbonylamino, halo C₁-C₆ alkylcarbonylamino, C₁-C₆ alkylaminocarbonyl or halo C₁-C₆ alkylaminocarbonyl.

The compound of the formula I, a stereoisomer, a cis-trans isomer, a tautomer thereof and a pharmaceutically acceptable salt thereof, further preferred compounds of the formula:

W is selected from NH;

X is selected from CH₂, O or NH;

Y is selected from O or S;

R¹ and R² are selected from COOH, CONHR¹⁰, —CONHSO₂R¹⁰, COOR¹⁰,

R³ is selected from the group consisting of H, C₁-C₂ alkyl, halo C₁-C₂ alkyl, C₂-C₄ alkenyl, halo C₂-C₄ alkenyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: phenyl, pyridyl;

R⁴ is selected from H or halogen;

R⁵ is selected from H or halogen;

R⁶ is selected from the group consisting of H, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ Alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₆ alkyl, heteroaryl C₁-C₃ alkyl, aryl C₁-C₃ alkoxy, heteroaryl C₁-C₃ alkoxy, aryloxy or heteroaryloxy;

R⁷ and R⁸ are the same or different and selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl, the following groups which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₃: alkyl, heteroaryl C₁-C₃ alkyl;

R⁹ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₃ alkyl, heteroaryl C₁-C₃ alkyl;

R¹⁰ is selected from the group consisting of C₁-C₃ alkyl, C₃-C₆ cycloalkyl, halo C₁-C₃ alkyl, halo C₃-C₆ cycloalkyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₃ alkyl, heteroaryl C₁-C₃ alkyl;

R¹¹ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₆ alkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkylthiol, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₂-C₆ alkenyl, halo C₂-C₆ alkenyl, C₃-C₆ alkenyloxy, halo C₃-C₆ alkenyloxy, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, C₃-C₆ alkynyloxy, halo C₃-C₆ alkynyloxy, halo C₁-C₆ alkylthiol, halo C₁-C₆ alkylcarbonyl, C₁-C₆ alkylamino, halo C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₁-C₆ alkylcarbonylamino, halo C₁-C₆ alkylcarbonylamino, C₁-C₆ alkylaminocarbonyl or halo C₁-C₆ alkylaminocarbonyl.

The compound of the formula I, a stereoisomer, a cis-trans isomer, a tautomer thereof and a pharmaceutically acceptable salt thereof, wherein a further preferred compound is:

W is selected from NH;

X is selected from CH₂, O or NH;

Y is selected from O or S;

R¹ and R² are selected from COOH,

CONHSO₂CH₃, CONHSO₂CF₃ or COOCH₂CH₃;

R³ is selected from H, CH₃, CH₂CH₃ or CF₃;

R⁴ is selected from H;

R⁵ is selected from H;

R⁶ is selected from H;

R⁷ and R⁸ are the same or different and selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

R⁹ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃₋₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₁-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₃ alkyl, heteroaryl C₁-C₃ alkyl;

R¹¹ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₃ alkyl, halo C₁-C₃ alkyl, C₁-C₃ alkoxy, halo C₁-C₃ alkoxy, C₁-C₃ alkylthiol, C₁-C₃ alkylcarbonyl, C₁-C₃ alkoxycarbonyl, C₂-C₃ alkenyl, halo C₂-C₃ alkenyl, C₃-C₆ alkenyloxy, halo C₃-C₆ alkenyloxy, C₂-C₃ alkynyl, halo C₂-C₃ alkynyl, C₃-C₆ alkynyloxy, halo C₃-C₆ alkynyloxy, halo C₁-C₃ alkylthiol, halo C₁-C₃ alkylcarbonyl, C₁-C₃ alkylamino, halo C₁-C₃ alkylamino, C₂-C₃ dialkylamino, C₁-C₃ alkylcarbonylamino, halo C₁-C₃ alkylcarbonylamino, C₁-C₃ alkylaminocarbonyl or halo C₁-C₃ alkylaminocarbonyl.

The compound of the formula I, a stereoisomer, a cis-trans isomer, a tautomer thereof and a pharmaceutically acceptable salt thereof, and a still further preferred compound of the formula:

W is selected from NH;

X is selected from CH₂, O or NH;

Y is selected from O or S;

R¹ and R² are selected from COOH,

CONHSO₂CH₃, CONHSO₂CF₃ or COOCH₂CH₃;

R³ is selected from H, CH₃, CH₂CH₃ or CF₃;

R⁴ is selected from H;

R⁵ is selected from H;

R⁶ is selected from H;

R⁷ and R⁶ are the same or different and selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl;

R⁹ is selected from the group consisting of phenyl, 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, 2,4-difluorophenyl, 2-fluoro-4-methylphenyl, 3-trifluoromethyl-4-chlorophenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-trifluoromethylphenyl, 3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 5-methylisoxazolyl.

The compound of the formula I, a stereoisomer, a cis-trans isomer, a tautomer thereof and a pharmaceutically acceptable salt thereof, and a still further preferred compound of the formula:

W is NH;

X is NH or CH₂;

Y is O;

R¹ and R² is selected from COOH,

or COOCH₂CH₃;

R³ is selected from CH₃;

R⁴ is selected from H;

R⁵ is selected from H;

R⁶ is selected from H;

R⁷ and R⁸ are the same or different and selected from n-butyl or isobutyl;

R⁹ is selected from the group consisting of 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,4-difluorophenyl, 2-fluoro-4-methylphenyl, 3-trifluoromethyl-4-chlorophenyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-fluorophenyl or 5-methylisoxazolyl.

The above pharmaceutically acceptable salt prepared by compound and base can be sodium salt, potassium salt, calcium salt, zinc salt, magnesium salt and other metal ion salt. It also can be meglumine salt, aminobutanediol salt, aminoethanol salt, lysine salt, arginine salt and other organic salt. Acid radical salt can be hydrochloride, sulfate, hydrobromate, mesylate, citrate, oxalate, succinate, maleate, citrate, acetate, lactate, phosphate, hydroiodate, nitrate, tartaric acid, p-toluene sulfonic acid, etc.

In the definition of compound of formula I, the terms are generally defined as follows:

Halogen: fluorine, chlorine, bromine or iodine.

Alkyl: straight or branched alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, or tert-butyl.

Cycloalkyl: a heterocyclic ring alkyl; such as cyclopropyl, cyclopentyl, or cyclohexyl, which is substituted or unsubstituted. Substituent group such as methyl, halogen, etc.

Heterocyclic alkyl: a ring alkyl substituted or unsubstituted containing one or more N, O, S heteroatoms, such as tetrahydrofuranyl or cyclopentanyl. Substituent group such as methyl, halogen, etc.

Halo alkyl: straight or branched alkyl, in which the hydrogen atoms may be partially or completely replaced by halo atoms, such as chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, etc.

Alkoxy: Straight or branched alkyl groups are linked to the structure by oxygen atom bonds.

Halo alkoxy: Straight or branched alkoxy groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms. For example, chloromethoxy, dichloromethoxy, trichloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chlorofluoromethoxy, trifluoroethoxy, etc.

Alkoxy alkyl: The alkoxy group is linked to the structure by alkyl group. Such as, —CH₂OCH₃, —CH₂OCH₂CH₃.

Halo alkoxy alkyl: The hydrogen atoms in alkoxyalkyl groups may be partially or completely replaced by halogen atoms. Such as, —CH₂OCH₂CH₂Cl.

Alkylthiol: Straight or branched alkyl groups that is bonded to a structure by an atomic sulfur bond.

Halo alkylthiol: Straight or branched alkylthiol groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms. For example, chloromethane, dichloromethane, trichloromethane, fluoromethane, difluoromethane, trifluoromethane, chlorofluoromethane, etc.

Alkylamino: Straight or branched alkyl groups bonded to a structure by a nitrogen atom.

Halo alkylamino: Straight or branched alkylamino groups in which the hydrogen atoms may be partially or completely replaced by the halogen atoms.

Alkenyl: Straight or branched alkenes groups, such as vinyl, 1-propylene, 2-propylene, and different butylene, pentenyl, and hexenyl isomers. Alkenes also include polyenes, such as 1,2-propylene, and 2,4-hexadienyl.

Halo alkene: Straight or branched alkenes groups in which hydrogen atoms may be partially or completely replaced by halogen atoms.

Alkynyl: Straight or branched alkynes groups, such as acetylenyl, 1-propargynyl, 2-propargynyl, and different butynyl, pentynyl, and hexynyl isomers. Alkynyl also includes groups consisting of multiple triple bonds, such as 2,5-hexylenyl.

Halo alkynyl: Straight or branched alkynes groups in which hydrogen atoms may be partially or completely replaced by halogen atoms.

Alkenyloxy: Straight or branched alkenyl groups bonded to a structure by an oxygen bond.

Halo alkenyloxy: Straight or branched alkenyl groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms.

Alkynyloxy: Straight or branched alkynyl groups bonded to a structure by an oxygen atom.

Halo alkynyloxy: Straight or branched alkynyl groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms.

Alkyl carbonyl: Straight or branched alkyl groups bonded to a structure by a carbonyl group (—CO—), such as an acetyl group.

Halo alkyl carbonyl: Straight or branched Alkyl carbonyl groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms.

Alkoxy carbonyl: Straight or branched alkoxy groups bonded to a structure by a carbonyl group (—CO—). Such as —COOCH₃, —COOCH₂CH₃.

Halo alkoxyl carbonyl: Straight or branched alkoxyl carbonyl groups in which the hydrogen atoms may be partially or completely replaced by halogen atoms. Such as —COOCH₂CF₃, —COOCH₂CH₂Cl etc.

Alkyl carbonyl amino: Such as —NHCOCH₃, —NHCOC(CH₃)₃

Alkyl aminocarbonyl: Such as —C(═O)NHCH₃, —C(═O)N(CH₃)₂

The aromatic parts of aryl, aryl alkyl, aryloxy, aryl aryloxy and aryl amino include phenyl or naphthalene group, etc.

Hetero aryl groups are five-membered rings or six-membered rings containing one or more N, O, S hetero atoms. For example, furanyl, pyrazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, etc.

Heteroaryl part of heteroaryl alkyl, heteroaryloxy and heteroaryl alkoxy groups refers to a five or a six-membered ring containing one or more N, O, S heteroatoms. For example, furyl, pyrazolyl, thiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, triazinyl, quinolyl, benzoxazolyl, indolyl, etc.

The application of a vinylarene derivative, the compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, or a combination thereof, in the preparation of an inhibitor for inhibiting the activity of IDO-1 enzyme.

The application of a vinylarene derivative, the compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, or a combination thereof, in the preparation of an anti-cancer drug, a viral infectious agent, a depressant, an organ transplant rejection agent or an autoimmune enhancer.

The cancer is colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia or melanoma.

A pharmaceutical composition comprising any one or more compounds shown in formula I, its stereoisomer, cis-trans isomer, tautomer, pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers or diluents.

The compounds in the present invention, stereoisomer can be formed by connecting different substituents with carbon-carbon double bond (Z and E are used to represent different configurations, respectively). The present invention includes Z-type isomer and E-type isomer and their mixtures in any proportion.

In formula I

the specific substituent is:

In formula I, the specific substituent of W is CH₂, O or NH;

In formula I, the specific substituent of X is CH₂, O or NH;

In formula I, the specific substituent of Y is O or S;

In formula I, the specific substituents in R³ are H, CH₃, CH₂CH₃, CH₂CH₂CH₃ and CF₃.

In formula I, the specific substituents of R⁴ are H, Cl, Br and I.

In formula I, the specific substituents of R⁵ are H, Cl, Br and I.

The specific substituents of R⁶ in formula I are shown in table 1,

TABLE I H Cl Br I NO₂ CN CH₃ CH₂CH₃ CH₂CH₂CH₃ CH₂CH₂CH₂CH₃ CH₂(CH₂)₃CH₃

In formula I, R¹ and R² are the same or different, and the specific substituents are shown in table 2. The definitions of other substituents in formula I, such as R³, R⁴ and R⁵, are the same as above.

TABLE 2 H COOH COOCH₂CH₃ CONHSO₂CH₃ CONHSO₂CF₃

In formula I, R⁷ and R⁸ are the same or different, and the specific substituents are shown in table 3. The definitions of other substituents in formula I, such as R³, R⁴ and R⁵, are the same as above.

TABLE 3 H CH₃ CH₂CH₃ CH₂CH₂CH₃

The specific substituents of R⁹ in formula I, are shown in table 4. The definitions of other substituents in formula I, such as R³, R⁴ and R⁵, are the same as above.

TABLE 4

In the present invention, the specific compound in formula I which inhibits the activity of the IDO enzyme is shown as formula II, The specific compound listed in table 5, but the present invention is not limited by these compounds

TABLE 5 Compound Number R¹ R³ R⁷ R⁸ R Y X 1 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-CH₃ O NH 2 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-CH₃ O NH 3 COOCH₂CH₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 4 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-F O NH 5 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-F O NH 6 COOCH₂CH₃ CH₃ n-butyl n-butyl 2,4-2F O NH 7 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 8 COOH CH₃ n-butyl n-butyl 2-CH₃ O NH 9 COOH CH₃ n-butyl n-butyl 4-CH₃ O NH 10 COOH CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 11 COOH CH₃ n-butyl n-butyl 2-F O NH 12 COOH CH₃ n-butyl n-butyl 4-F O NH 13 COOH CH₃ n-butyl n-butyl 2,4-2F O NH 14 COOH CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 15 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-CH₃ O NH 16 CONHSO₂CH₃ CH₃ n-butyl n-butyl 4-CH₃ O NH 17 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 18 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-F O NH 19 CONHSO₂CH₃ CH₃ n-butyl n-butyl 4-F O NH 20 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2,4-2F O NH 21 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 22 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-CH₃ O NH 23 CONHSO₂CF₃ CH₃ n-butyl n-butyl 4-CH₃ O NH 24 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 25 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-F O NH 26 CONHSO₂CF₃ CH₃ n-butyl n-butyl 4-F O NH 27 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2,4-2F O NH 28 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 29 5-tetrazolyl CH₃ n-butyl n-butyl 2-CH₃ O NH 30 5-tetrazolyl CH₃ n-butyl n-butyl 4-CH₃ O NH 31 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 32 5-tetrazolyl CH₃ n-butyl n-butyl 2-F O NH 33 5-tetrazolyl CH₃ n-butyl n-butyl 4-F O NH 34 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2F O NH 35 5-tetrazolyl CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 36 5-tetrazolyl CH₃ n-butyl n-butyl 2-CH₃ O NH 37 5-tetrazolyl CH₃ n-butyl n-butyl 4-CH₃ O NH 38 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 39 5-tetrazolyl CH₃ n-butyl n-butyl 2-F O NH 40 5-tetrazolyl CH₃ n-butyl n-butyl 4-F O NH 41 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2F O NH 42 5-tetrazolyl CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 43 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-CH₃ O NH 44 COOCH₂CH₃ CH₃ isobutyl isobutyl 4-CH₃ O NH 45 COOCH₂CH₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 46 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-F O NH 47 COOCH₂CH₃ CH₃ isobutyl isobutyl 4-F O NH 48 COOCH₂CH₃ CH₃ isobutyl isobutyl 2,4-2F O NH 49 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 50 COOH CH₃ isobutyl isobutyl 2-CH₃ O NH 51 COOH CH₃ isobutyl isobutyl 4-CH₃ O NH 52 COOH CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 53 COOH CH₃ isobutyl isobutyl 2-F O NH 54 COOH CH₃ isobutyl isobutyl 4-F O NH 55 COOH CH₃ isobutyl isobutyl 2,4-2F O NH 56 COOH CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 57 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-CH₃ O NH 58 CONHSO₂CH₃ CH₃ isobutyl isobutyl 4-CH₃ O NH 59 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 60 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-F O NH 61 CONHSO₂CH₃ CH₃ isobutyl isobutyl 4-F O NH 62 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2,4-2F O NH 63 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 64 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-CH₃ O NH 65 CONHSO₂CF₃ CH₃ isobutyl isobutyl 4-CH₃ O NH 66 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 67 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-F O NH 68 CONHSO₂CF₃ CH₃ isobutyl isobutyl 4-F O NH 69 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2,4-2F O NH 70 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 71 5-tetrazolyl CH₃ isobutyl isobutyl 2-CH₃ O NH 72 5-tetrazolyl CH₃ isobutyl isobutyl 4-CH₃ O NH 73 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 74 5-tetrazolyl CH₃ isobutyl isobutyl 2-F O NH 75 5-tetrazolyl CH₃ isobutyl isobutyl 4-F O NH 76 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2F O NH 77 5-tetrazolyl CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 78 5-tetrazolyl CH₃ isobutyl isobutyl 2-CH₃ O NH 79 5-tetrazolyl CH₃ isobutyl isobutyl 4-CH₃ O NH 80 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 81 5-tetrazolyl CH₃ isobutyl isobutyl 2-F O NH 82 5-tetrazolyl CH₃ isobutyl isobutyl 4-F O NH 83 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2F O NH 84 5-tetrazolyl CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 85 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-CH₃ O NH 86 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 4-CH₃ O NH 87 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 88 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-F O NH 89 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 4-F O NH 90 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2F O NH 91 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 92 COOH CH₃ cyclohexyl isobutyl 2-CH₃ O NH 93 COOH CH₃ cyclohexyl isobutyl 4-CH₃ O NH 94 COOH CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 95 COOH CH₃ cyclohexyl isobutyl 2-F O NH 96 COOH CH₃ cyclohexyl isobutyl 4-F O NH 97 COOH CH₃ cyclohexyl isobutyl 2,4-2F O NH 98 COOH CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 99 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-CH₃ O NH 100 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 4-CH₃ O NH 101 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 102 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-F O NH 103 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 4-F O NH 104 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2F O NH 105 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 106 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-CH₃ O NH 107 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 4-CH₃ O NH 108 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 109 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-F O NH 110 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 4-F O NH 111 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2,4-2F O NH 112 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 113 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-CH₃ O NH 114 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-CH₃ O NH 115 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 116 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F O NH 117 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-F O NH 118 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2F O NH 119 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 120 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-CH₃ O NH 121 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-CH₃ O NH 122 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 123 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F O NH 124 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-F O NH 125 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2F O NH 126 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 127 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O NH 128 COOCH₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O NH 129 COOCH₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 130 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-F O NH 131 COOCH₂CH₃ CF₃ n-butyl n-butyl 4-F O NH 132 COOCH₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O NH 133 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 134 COOH CF₃ n-butyl n-butyl 2-CH₃ O NH 135 COOH CF₃ n-butyl n-butyl 4-CH₃ O NH 136 COOH CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 137 COOH CF₃ n-butyl n-butyl 2-F O NH 138 COOH CF₃ n-butyl n-butyl 4-F O NH 139 COOH CF₃ n-butyl n-butyl 2,4-2F O NH 140 COOH CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 141 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O NH 142 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O NH 143 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 144 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F O NH 145 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-F O NH 146 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O NH 147 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 148 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-CH₃ O NH 149 CONHSO₂CF₃ CF₃ n-butyl n-butyl 4-CH₃ O NH 150 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 151 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-F O NH 152 CONHSO₂CF₃ CF₃ n-butyl n-butyl 4-F O NH 153 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2,4-2F O NH 154 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 155 5-tetrazolyl CF₃ n-butyl n-butyl 2-CH₃ O NH 156 5-tetrazolyl CF₃ n-butyl n-butyl 4-CH₃ O NH 157 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 158 5-tetrazolyl CF₃ n-butyl n-butyl 2-F O NH 159 5-tetrazolyl CF₃ n-butyl n-butyl 4-F O NH 160 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2F O NH 161 5-tetrazolyl CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 162 5-tetrazolyl CF₃ n-butyl n-butyl 2-CH₃ O NH 163 5-tetrazolyl CF₃ n-butyl n-butyl 4-CH₃ O NH 164 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 165 5-tetrazolyl CF₃ n-butyl n-butyl 2-F O NH 166 5-tetrazolyl CF₃ n-butyl n-butyl 4-F O NH 167 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2F O NH 168 5-tetrazolyl CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 169 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O NH 170 COOCH₂CH₃ CF₃ isobutyl isobutyl 4-CH₃ O NH 171 COOCH₂CH₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 172 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-F O NH 173 COOCH₂CH₃ CF₃ isobutyl isobutyl 4-F O NH 174 COOCH₂CH₃ CF₃ isobutyl isobutyl 2,4-2F O NH 175 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 176 COOH CF₃ isobutyl isobutyl 2-CH₃ O NH 177 COOH CF₃ isobutyl isobutyl 4-CH₃ O NH 178 COOH CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 179 COOH CF₃ isobutyl isobutyl 2-F O NH 180 COOH CF₃ isobutyl isobutyl 4-F O NH 181 COOH CF₃ isobutyl isobutyl 2,4-2F O NH 182 COOH CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 183 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O NH 184 CONHSO₂CH₃ CF₃ isobutyl isobutyl 4-CH₃ O NH 185 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 186 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-F O NH 187 CONHSO₂CH₃ CF₃ isobutyl isobutyl 4-F O NH 188 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2,4-2F O NH 189 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 190 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-CH₃ O NH 191 CONHSO₂CF₃ CF₃ isobutyl isobutyl 4-CH₃ O NH 192 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 193 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-F O NH 194 CONHSO₂CF₃ CF₃ isobutyl isobutyl 4-F O NH 195 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2,4-2F O NH 196 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 197 5-tetrazolyl CF₃ isobutyl isobutyl 2-CH₃ O NH 198 5-tetrazolyl CF₃ isobutyl isobutyl 4-CH₃ O NH 199 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 200 5-tetrazolyl CF₃ isobutyl isobutyl 2-F O NH 201 5-tetrazolyl CF₃ isobutyl isobutyl 4-F O NH 202 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2F O NH 203 5-tetrazolyl CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 204 5-tetrazolyl CF₃ isobutyl isobutyl 2-CH₃ O NH 205 5-tetrazolyl CF₃ isobutyl isobutyl 4-CH₃ O NH 206 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 207 5-tetrazolyl CF₃ isobutyl isobutyl 2-F O NH 208 5-tetrazolyl CF₃ isobutyl isobutyl 4-F O NH 209 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2F O NH 210 5-tetrazolyl CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 211 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-CH₃ O NH 212 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 4-CH₃ O NH 213 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 214 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-F O NH 215 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 4-F O NH 216 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2F O NH 217 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 218 COOH CF₃ cyclohexyl isobutyl 2-CH₃ O NH 219 COOH CF₃ cyclohexyl isobutyl 4-CH₃ O NH 220 COOH CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 221 COOH CF₃ cyclohexyl isobutyl 2-F O NH 222 COOH CF₃ cyclohexyl isobutyl 4-F O NH 223 COOH CF₃ cyclohexyl isobutyl 2,4-2F O NH 224 COOH CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 225 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-CH₃ O NH 226 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 4-CH₃ O NH 227 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 228 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-F O NH 229 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 4-F O NH 230 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2F O NH 231 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 232 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-CH₃ O NH 233 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 4-CH₃ O NH 234 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 235 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-F O NH 236 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 4-F O NH 237 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2,4-2F O NH 238 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 239 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-CH₃ O NH 240 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-CH₃ O NH 241 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 242 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F O NH 243 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-F O NH 244 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2F O NH 245 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 246 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-CH₃ O NH 247 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-CH₃ O NH 248 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 249 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F O NH 250 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-F O NH 251 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2F O NH 252 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 253 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 254 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 255 COOCH₂CH₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 256 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-F O CH₂ 257 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-F O CH₂ 258 COOCH₂CH₃ CH₃ n-butyl n-butyl 2,4-2F O CH₂ 259 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 260 COOH CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 261 COOH CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 262 COOH CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 263 COOH CH₃ n-butyl n-butyl 2-F O CH₂ 264 COOH CH₃ n-butyl n-butyl 4-F O CH₂ 265 COOH CH₃ n-butyl n-butyl 2,4-2F O CH₂ 266 COOH CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 267 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 268 CONHSO₂CH₃ CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 269 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 270 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-F O CH₂ 271 CONHSO₂CH₃ CH₃ n-butyl n-butyl 4-F O CH₂ 272 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2,4-2F O CH₂ 273 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 274 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 275 CONHSO₂CF₃ CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 276 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2,4-2CH3 O CH₂ 277 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-F O CH₂ 278 CONHSO₂CF₃ CH₃ n-butyl n-butyl 4-F O CH₂ 279 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2,4-2F O CH₂ 280 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 281 5-tetrazolyl CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 282 5-tetrazolyl CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 283 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 284 5-tetrazolyl CH₃ n-butyl n-butyl 2-F O CH₂ 285 5-tetrazolyl CH₃ n-butyl n-butyl 4-F O CH₂ 286 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2F O CH₂ 287 5-tetrazolyl CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 288 5-tetrazolyl CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 289 5-tetrazolyl CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 290 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 291 5-tetrazolyl CH₃ n-butyl n-butyl 2-F O CH₂ 292 5-tetrazolyl CH₃ n-butyl n-butyl 4-F O CH₂ 293 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2F O CH₂ 294 5-tetrazolyl CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 295 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 296 COOCH₂CH₃ CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 297 COOCH₂CH₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 298 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-F O CH₂ 299 COOCH₂CH₃ CH₃ isobutyl isobutyl 4-F O CH₂ 300 COOCH₂CH₃ CH₃ isobutyl isobutyl 2,4-2F O CH₂ 301 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 302 COOH CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 303 COOH CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 304 COOH CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 305 COOH CH₃ isobutyl isobutyl 2-F O CH₂ 306 COOH CH₃ isobutyl isobutyl 4-F O CH₂ 307 COOH CH₃ isobutyl isobutyl 2,4-2F O CH₂ 308 COOH CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 309 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 310 CONHSO₂CH₃ CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 311 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 312 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-F O CH₂ 313 CONHSO₂CH₃ CH₃ isobutyl isobutyl 4-F O CH₂ 314 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2,4-2F O CH₂ 315 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 316 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 317 CONHSO₂CF₃ CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 318 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 319 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-F O CH₂ 320 CONHSO₂CF₃ CH₃ isobutyl isobutyl 4-F O CH₂ 321 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2,4-2F O CH₂ 322 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 323 5-tetrazolyl CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 324 5-tetrazolyl CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 325 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 326 5-tetrazolyl CH₃ isobutyl isobutyl 2-F O CH₂ 327 5-tetrazolyl CH₃ isobutyl isobutyl 4-F O CH₂ 328 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2F O CH₂ 329 5-tetrazolyl CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 330 5-tetrazolyl CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 331 5-tetrazolyl CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 332 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 333 5-tetrazolyl CH₃ isobutyl isobutyl 2-F O CH₂ 334 5-tetrazolyl CH₃ isobutyl isobutyl 4-F O CH₂ 335 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2F O CH₂ 336 5-tetrazolyl CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 337 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 338 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 339 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 340 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-F O CH₂ 341 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 4-F O CH₂ 342 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 343 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 344 COOH CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 345 COOH CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 346 COOH CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 347 COOH CH₃ cyclohexyl isobutyl 2-F O CH₂ 348 COOH CH₃ cyclohexyl isobutyl 4-F O CH₂ 349 COOH CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 350 COOH CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 351 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 352 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 353 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 354 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-F O CH₂ 355 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 4-F O CH₂ 356 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 357 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 358 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 359 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 360 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 361 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-F O CH₂ 362 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 4-F O CH₂ 363 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 364 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 365 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 366 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 367 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 368 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F O CH₂ 369 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-F O CH₂ 370 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 371 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 372 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 373 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 374 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 375 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F O CH₂ 376 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-F O CH₂ 377 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 378 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 379 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 380 COOCH₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 381 COOCH₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 382 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-F O CH₂ 383 COOCH₂CH₃ CF₃ n-butyl n-butyl 4-F O CH₂ 384 COOCH₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O CH₂ 385 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 386 COOH CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 387 COOH CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 388 COOH CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 389 COOH CF₃ n-butyl n-butyl 2-F O CH₂ 390 COOH CF₃ n-butyl n-butyl 4-F O CH₂ 391 COOH CF₃ n-butyl n-butyl 2,4-2F O CH₂ 392 COOH CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 393 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 394 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 395 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 396 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F O CH₂ 397 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-F O CH₂ 398 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O CH₂ 399 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 400 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 401 CONHSO₂CF₃ CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 402 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2,4-2CH3 O CH₂ 403 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-F O CH₂ 404 CONHSO₂CF₃ CF₃ n-butyl n-butyl 4-F O CH₂ 405 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2,4-2F O CH₂ 406 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 407 5-tetrazolyl CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 408 5-tetrazolyl CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 409 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 410 5-tetrazolyl CF₃ n-butyl n-butyl 2-F O CH₂ 411 5-tetrazolyl CF₃ n-butyl n-butyl 4-F O CH₂ 412 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2F O CH₂ 413 5-tetrazolyl CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 414 5-tetrazolyl CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 415 5-tetrazolyl CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 416 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 417 5-tetrazolyl CF₃ n-butyl n-butyl 2-F O CH₂ 418 5-tetrazolyl CF₃ n-butyl n-butyl 4-F O CH₂ 419 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2F O CH₂ 420 5-tetrazolyl CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 421 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 422 COOCH₂CH₃ CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 423 COOCH₂CH₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 424 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-F O CH₂ 425 COOCH₂CH₃ CF₃ isobutyl isobutyl 4-F O CH₂ 426 COOCH₂CH₃ CF₃ isobutyl isobutyl 2,4-2F O CH₂ 427 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 428 COOH CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 429 COOH CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 430 COOH CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 431 COOH CF₃ isobutyl isobutyl 2-F O CH₂ 432 COOH CF₃ isobutyl isobutyl 4-F O CH₂ 433 COOH CF₃ isobutyl isobutyl 2,4-2F O CH₂ 434 COOH CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 435 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 436 CONHSO₂CH₃ CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 437 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 438 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-F O CH₂ 439 CONHSO₂CH₃ CF₃ isobutyl isobutyl 4-F O CH₂ 440 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2,4-2F O CH₂ 441 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 442 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 443 CONHSO₂CF₃ CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 444 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 445 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-F O CH₂ 446 CONHSO₂CF₃ CF₃ isobutyl isobutyl 4-F O CH₂ 447 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2,4-2F O CH₂ 448 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 449 5-tetrazolyl CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 450 5-tetrazolyl CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 451 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 452 5-tetrazolyl CF₃ isobutyl isobutyl 2-F O CH₂ 453 5-tetrazolyl CF₃ isobutyl isobutyl 4-F O CH₂ 454 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2F O CH₂ 455 5-tetrazolyl CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 456 5-tetrazolyl CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 457 5-tetrazolyl CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 458 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 459 5-tetrazolyl CF₃ isobutyl isobutyl 2-F O CH₂ 460 5-tetrazolyl CF₃ isobutyl isobutyl 4-F O CH₂ 461 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2F O CH₂ 462 5-tetrazolyl CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 463 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 464 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 465 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 466 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-F O CH₂ 467 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 4-F O CH₂ 468 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 469 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 470 COOH CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 471 COOH CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 472 COOH CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 473 COOH CF₃ cyclohexyl isobutyl 2-F O CH₂ 474 COOH CF₃ cyclohexyl isobutyl 4-F O CH₂ 475 COOH CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 476 COOH CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 477 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 478 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 479 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 480 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-F O CH₂ 481 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 4-F O CH₂ 482 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 483 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 484 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 485 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 486 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 487 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-F O CH₂ 488 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 4-F O CH₂ 489 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 490 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 491 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 492 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 493 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 494 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F O CH₂ 495 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-F O CH₂ 496 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 497 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 498 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 499 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 500 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 501 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F O CH₂ 502 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-F O CH₂ 503 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 504 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 505 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-Cl O NH 506 COOCH₂CH₃ CH₃ n-butyl n-butyl 3-Cl O NH 507 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-Cl O NH 508 COOCH₂CH₃ CH₃ n-butyl n-butyl 3-CF₃-4-Cl O NH 509 COOCH₂CH₃ CH₃ n-butyl n-butyl H S NH 510 COOCH₂CH₃ CH₃ n-butyl n-butyl 3-CH₃ O NH 511 COOH CH₃ n-butyl n-butyl 2-Cl O NH 512 COOH CH₃ n-butyl n-butyl 3-Cl O NH 513 COOH CH₃ n-butyl n-butyl 4-Cl O NH 514 COOH CH₃ n-butyl n-butyl 3-CF₃-4-Cl O NH 515 COOH CH₃ n-butyl n-butyl H S NH 516 COOH CH₃ n-butyl n-butyl 3-CH₃ O NH

In the present invention, the specific compound in formula I which inhibits the activity of the IDO enzyme is shown as formula III, The specific compound listed in table 6, but the present invention is not limited by these compounds.

TABLE 6 Compound Number R² R¹ R⁷ R⁸ R Y X 517 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-CH₃ O NH 518 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-CH₃ O NH 519 COOCH₂CH₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 520 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-F O NH 521 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-F O NH 522 COOCH₂CH₃ CH₃ n-butyl n-butyl 2,4-2F O NH 523 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 524 COOH CH₃ n-butyl n-butyl 2-CH₃ O NH 525 COOH CH₃ n-butyl n-butyl 4-CH₃ O NH 526 COOH CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 527 COOH CH₃ n-butyl n-butyl 2-F O NH 528 COOH CH₃ n-butyl n-butyl 4-F O NH 529 COOH CH₃ n-butyl n-butyl 2,4-2F O NH 530 COOH CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 531 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-CH₃ O NH 532 CONHSO₂CH₃ CH₃ n-butyl n-butyl 4-CH₃ O NH 533 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 534 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-F O NH 535 CONHSO₂CH₃ CH₃ n-butyl n-butyl 4-F O NH 536 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2,4-2F O NH 537 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 538 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-CH₃ O NH 539 CONHSO₂CF₃ CH₃ n-butyl n-butyl 4-CH₃ O NH 540 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 541 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-F O NH 542 CONHSO₂CF₃ CH₃ n-butyl n-butyl 4-F O NH 543 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2,4-2F O NH 544 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 545 5-tetrazolyl CH₃ n-butyl n-butyl 2-CH₃ O NH 546 5-tetrazolyl CH₃ n-butyl n-butyl 4-CH₃ O NH 547 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 548 5-tetrazolyl CH₃ n-butyl n-butyl 2-F O NH 549 5-tetrazolyl CH₃ n-butyl n-butyl 4-F O NH 550 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2F O NH 551 5-tetrazolyl CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 552 5-tetrazolyl CH₃ n-butyl n-butyl 2-CH₃ O NH 553 5-tetrazolyl CH₃ n-butyl n-butyl 4-CH₃ O NH 554 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2CH₃ O NH 555 5-tetrazolyl CH₃ n-butyl n-butyl 2-F O NH 556 5-tetrazolyl CH₃ n-butyl n-butyl 4-F O NH 557 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2F O NH 558 5-tetrazolyl CH₃ n-butyl n-butyl 2-F-4-CH₃ O NH 559 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-CH₃ O NH 560 COOCH₂CH₃ CH₃ isobutyl isobutyl 4-CH₃ O NH 561 COOCH₂CH₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 562 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-F O NH 563 COOCH₂CH₃ CH₃ isobutyl isobutyl 4-F O NH 564 COOCH₂CH₃ CH₃ isobutyl isobutyl 2,4-2F O NH 565 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 566 COOH CH₃ isobutyl isobutyl 2-CH₃ O NH 567 COOH CH₃ isobutyl isobutyl 4-CH₃ O NH 568 COOH CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 569 COOH CH₃ isobutyl isobutyl 2-F O NH 570 COOH CH₃ isobutyl isobutyl 4-F O NH 571 COOH CH₃ isobutyl isobutyl 2,4-2F O NH 572 COOH CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 573 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-CH₃ O NH 574 CONHSO₂CH₃ CH₃ isobutyl isobutyl 4-CH₃ O NH 575 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 576 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-F O NH 577 CONHSO₂CH₃ CH₃ isobutyl isobutyl 4-F O NH 578 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2,4-2F O NH 579 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 580 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-CH₃ O NH 581 CONHSO₂CF₃ CH₃ isobutyl isobutyl 4-CH₃ O NH 582 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 583 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-F O NH 584 CONHSO₂CF₃ CH₃ isobutyl isobutyl 4-F O NH 585 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2,4-2F O NH 586 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 587 5-tetrazolyl CH₃ isobutyl isobutyl 2-CH₃ O NH 588 5-tetrazolyl CH₃ isobutyl isobutyl 4-CH₃ O NH 589 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 590 5-tetrazolyl CH₃ isobutyl isobutyl 2-F O NH 591 5-tetrazolyl CH₃ isobutyl isobutyl 4-F O NH 592 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2F O NH 593 5-tetrazolyl CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 594 5-tetrazolyl CH₃ isobutyl isobutyl 2-CH₃ O NH 595 5-tetrazolyl CH₃ isobutyl isobutyl 4-CH₃ O NH 596 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2CH₃ O NH 597 5-tetrazolyl CH₃ isobutyl isobutyl 2-F O NH 598 5-tetrazolyl CH₃ isobutyl isobutyl 4-F O NH 599 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2F O NH 600 5-tetrazolyl CH₃ isobutyl isobutyl 2-F-4-CH₃ O NH 601 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-CH₃ O NH 602 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 4-CH₃ O NH 603 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 604 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-F O NH 605 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 4-F O NH 606 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2F O NH 607 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 608 COOH CH₃ cyclohexyl isobutyl 2-CH₃ O NH 609 COOH CH₃ cyclohexyl isobutyl 4-CH₃ O NH 610 COOH CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 611 COOH CH₃ cyclohexyl isobutyl 2-F O NH 612 COOH CH₃ cyclohexyl isobutyl 4-F O NH 613 COOH CH₃ cyclohexyl isobutyl 2,4-2F O NH 614 COOH CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 615 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-CH₃ O NH 616 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 4-CH₃ O NH 617 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 618 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-F O NH 619 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 4-F O NH 620 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2F O NH 621 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 622 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-CH₃ O NH 623 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 4-CH₃ O NH 624 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 625 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-F O NH 626 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 4-F O NH 627 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2,4-2F O NH 628 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 629 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-CH₃ O NH 630 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-CH₃ O NH 631 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 632 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F O NH 633 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-F O NH 634 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2F O NH 635 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 636 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-CH₃ O NH 637 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-CH₃ O NH 638 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 639 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F O NH 640 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-F O NH 641 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2F O NH 642 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 643 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O NH 644 COOCH₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O NH 645 COOCH₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 646 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-F O NH 647 COOCH₂CH₃ CF₃ n-butyl n-butyl 4-F O NH 648 COOCH₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O NH 649 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 650 COOH CF₃ n-butyl n-butyl 2-CH₃ O NH 651 COOH CF₃ n-butyl n-butyl 4-CH₃ O NH 652 COOH CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 653 COOH CF₃ n-butyl n-butyl 2-F O NH 654 COOH CF₃ n-butyl n-butyl 4-F O NH 655 COOH CF₃ n-butyl n-butyl 2,4-2F O NH 656 COOH CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 657 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O NH 658 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O NH 659 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 660 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F O NH 661 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-F O NH 662 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O NH 663 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 664 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-CH₃ O NH 665 CONHSO₂CF₃ CF₃ n-butyl n-butyl 4-CH₃ O NH 666 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 667 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-F O NH 668 CONHSO₂CF₃ CF₃ n-butyl n-butyl 4-F O NH 669 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2,4-2F O NH 670 CONHSO₂CF₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 671 5-tetrazolyl CF₃ n-butyl n-butyl 2-CH₃ O NH 672 5-tetrazolyl CF₃ n-butyl n-butyl 4-CH₃ O NH 673 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 674 5-tetrazolyl CF₃ n-butyl n-butyl 2-F O NH 675 5-tetrazolyl CF₃ n-butyl n-butyl 4-F O NH 676 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2F O NH 677 5-tetrazolyl CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 678 5-tetrazolyl CF₃ n-butyl n-butyl 2-CH₃ O NH 679 5-tetrazolyl CF₃ n-butyl n-butyl 4-CH₃ O NH 680 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2CH₃ O NH 681 5-tetrazolyl CF₃ n-butyl n-butyl 2-F O NH 682 5-tetrazolyl CF₃ n-butyl n-butyl 4-F O NH 683 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2F O NH 684 5-tetrazolyl CF₃ n-butyl n-butyl 2-F-4-CH₃ O NH 685 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O NH 686 COOCH₂CH₃ CF₃ isobutyl isobutyl 4-CH₃ O NH 687 COOCH₂CH₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 688 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-F O NH 689 COOCH₂CH₃ CF₃ isobutyl isobutyl 4-F O NH 690 COOCH₂CH₃ CF₃ isobutyl isobutyl 2,4-2F O NH 691 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 692 COOH CF₃ isobutyl isobutyl 2-CH₃ O NH 693 COOH CF₃ isobutyl isobutyl 4-CH₃ O NH 694 COOH CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 695 COOH CF₃ isobutyl isobutyl 2-F O NH 696 COOH CF₃ isobutyl isobutyl 4-F O NH 697 COOH CF₃ isobutyl isobutyl 2,4-2F O NH 698 COOH CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 699 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O NH 700 CONHSO₂CH₃ CF₃ isobutyl isobutyl 4-CH₃ O NH 701 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 702 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-F O NH 703 CONHSO₂CH₃ CF₃ isobutyl isobutyl 4-F O NH 704 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2,4-2F O NH 705 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 706 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-CH₃ O NH 707 CONHSO₂CF₃ CF₃ isobutyl isobutyl 4-CH₃ O NH 708 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 709 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-F O NH 710 CONHSO₂CF₃ CF₃ isobutyl isobutyl 4-F O NH 711 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2,4-2F O NH 712 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 713 5-tetrazolyl CF₃ isobutyl isobutyl 2-CH₃ O NH 714 5-tetrazolyl CF₃ isobutyl isobutyl 4-CH₃ O NH 715 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 716 5-tetrazolyl CF₃ isobutyl isobutyl 2-F O NH 717 5-tetrazolyl CF₃ isobutyl isobutyl 4-F O NH 718 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2F O NH 719 5-tetrazolyl CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 720 5-tetrazolyl CF₃ isobutyl isobutyl 2-CH₃ O NH 721 5-tetrazolyl CF₃ isobutyl isobutyl 4-CH₃ O NH 722 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2CH₃ O NH 723 5-tetrazolyl CF₃ isobutyl isobutyl 2-F O NH 724 5-tetrazolyl CF₃ isobutyl isobutyl 4-F O NH 725 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2F O NH 726 5-tetrazolyl CF₃ isobutyl isobutyl 2-F-4-CH₃ O NH 727 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-CH₃ O NH 728 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 4-CH₃ O NH 729 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 730 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-F O NH 731 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 4-F O NH 732 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2F O NH 733 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 734 COOH CF₃ cyclohexyl isobutyl 2-CH₃ O NH 735 COOH CF₃ cyclohexyl isobutyl 4-CH₃ O NH 736 COOH CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 737 COOH CF₃ cyclohexyl isobutyl 2-F O NH 738 COOH CF₃ cyclohexyl isobutyl 4-F O NH 739 COOH CF₃ cyclohexyl isobutyl 2,4-2F O NH 740 COOH CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 741 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-CH₃ O NH 742 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 4-CH₃ O NH 743 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 744 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-F O NH 745 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 4-F O NH 746 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2F O NH 747 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 748 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-CH₃ O NH 749 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 4-CH₃ O NH 750 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 751 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-F O NH 752 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 4-F O NH 753 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2,4-2F O NH 754 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 755 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-CH₃ O NH 756 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-CH₃ O NH 757 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 758 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F O NH 759 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-F O NH 760 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2F O NH 761 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 762 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-CH₃ O NH 763 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-CH₃ O NH 764 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2CH₃ O NH 765 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F O NH 766 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-F O NH 767 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2F O NH 768 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O NH 769 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 770 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 771 COOCH₂CH₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 772 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-F O CH₂ 773 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-F O CH₂ 774 COOCH₂CH₃ CH₃ n-butyl n-butyl 2,4-2F O CH₂ 775 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 776 COOH CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 777 COOH CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 778 COOH CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 779 COOH CH₃ n-butyl n-butyl 2-F O CH₂ 780 COOH CH₃ n-butyl n-butyl 4-F O CH₂ 781 COOH CH₃ n-butyl n-butyl 2,4-2F O CH₂ 782 COOH CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 783 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 784 CONHSO₂CH₃ CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 785 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 786 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-F O CH₂ 787 CONHSO₂CH₃ CH₃ n-butyl n-butyl 4-F O CH₂ 788 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2,4-2F O CH₂ 789 CONHSO₂CH₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 790 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 791 CONHSO₂CF₃ CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 792 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 793 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-F O CH₂ 794 CONHSO₂CF₃ CH₃ n-butyl n-butyl 4-F O CH₂ 795 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2,4-2F O CH₂ 796 CONHSO₂CF₃ CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 797 5-tetrazolyl CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 798 5-tetrazolyl CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 799 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 800 5-tetrazolyl CH₃ n-butyl n-butyl 2-F O CH₂ 801 5-tetrazolyl CH₃ n-butyl n-butyl 4-F O CH₂ 802 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2F O CH₂ 803 5-tetrazolyl CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 804 5-tetrazolyl CH₃ n-butyl n-butyl 2-CH₃ O CH₂ 805 5-tetrazolyl CH₃ n-butyl n-butyl 4-CH₃ O CH₂ 806 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 807 5-tetrazolyl CH₃ n-butyl n-butyl 2-F O CH₂ 808 5-tetrazolyl CH₃ n-butyl n-butyl 4-F O CH₂ 809 5-tetrazolyl CH₃ n-butyl n-butyl 2,4-2F O CH₂ 810 5-tetrazolyl CH₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 811 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 812 COOCH₂CH₃ CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 813 COOCH₂CH₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 814 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-F O CH₂ 815 COOCH₂CH₃ CH₃ isobutyl isobutyl 4-F O CH₂ 816 COOCH₂CH₃ CH₃ isobutyl isobutyl 2,4-2F O CH₂ 817 COOCH₂CH₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 818 COOH CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 819 COOH CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 820 COOH CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 821 COOH CH₃ isobutyl isobutyl 2-F O CH₂ 822 COOH CH₃ isobutyl isobutyl 4-F O CH₂ 823 COOH CH₃ isobutyl isobutyl 2,4-2F O CH₂ 824 COOH CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 825 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 826 CONHSO₂CH₃ CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 827 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 828 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-F O CH₂ 829 CONHSO₂CH₃ CH₃ isobutyl isobutyl 4-F O CH₂ 830 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2,4-2F O CH₂ 831 CONHSO₂CH₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 832 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 833 CONHSO₂CF₃ CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 834 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 835 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-F O CH₂ 836 CONHSO₂CF₃ CH₃ isobutyl isobutyl 4-F O CH₂ 837 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2,4-2F O CH₂ 838 CONHSO₂CF₃ CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 839 5-tetrazolyl CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 840 5-tetrazolyl CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 841 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 842 5-tetrazolyl CH₃ isobutyl isobutyl 2-F O CH₂ 843 5-tetrazolyl CH₃ isobutyl isobutyl 4-F O CH₂ 844 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2F O CH₂ 845 5-tetrazolyl CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 846 5-tetrazolyl CH₃ isobutyl isobutyl 2-CH₃ O CH₂ 847 5-tetrazolyl CH₃ isobutyl isobutyl 4-CH₃ O CH₂ 848 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 849 5-tetrazolyl CH₃ isobutyl isobutyl 2-F O CH₂ 850 5-tetrazolyl CH₃ isobutyl isobutyl 4-F O CH₂ 851 5-tetrazolyl CH₃ isobutyl isobutyl 2,4-2F O CH₂ 852 5-tetrazolyl CH₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 853 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 854 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 855 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 856 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-F O CH₂ 857 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 4-F O CH₂ 858 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 859 COOCH₂CH₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 860 COOH CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 861 COOH CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 862 COOH CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 863 COOH CH₃ cyclohexyl isobutyl 2-F O CH₂ 864 COOH CH₃ cyclohexyl isobutyl 4-F O CH₂ 865 COOH CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 866 COOH CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 867 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 868 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 869 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 870 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-F O CH₂ 871 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 4-F O CH₂ 872 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 873 CONHSO₂CH₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 874 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 875 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 876 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 877 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-F O CH₂ 878 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 4-F O CH₂ 879 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 880 CONHSO₂CF₃ CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 881 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 882 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 883 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 884 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F O CH₂ 885 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-F O CH₂ 886 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 887 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 888 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 889 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 890 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 891 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F O CH₂ 892 5-tetrazolyl CH₃ cyclohexyl isobutyl 4-F O CH₂ 893 5-tetrazolyl CH₃ cyclohexyl isobutyl 2,4-2F O CH₂ 894 5-tetrazolyl CH₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 895 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 896 COOCH₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 897 COOCH₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 898 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-F O CH₂ 899 COOCH₂CH₃ CF₃ n-butyl n-butyl 4-F O CH₂ 900 COOCH₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O CH₂ 901 COOCH₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 902 COOH CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 903 COOH CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 904 COOH CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 905 COOH CF₃ n-butyl n-butyl 2-F O CH₂ 906 COOH CF₃ n-butyl n-butyl 4-F O CH₂ 907 COOH CF₃ n-butyl n-butyl 2,4-2F O CH₂ 908 COOH CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 909 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 910 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 911 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 912 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F O CH₂ 913 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-F O CH₂ 914 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O CH₂ 915 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 916 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 917 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 918 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2CH3 O CH₂ 919 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F O CH₂ 920 CONHSO₂CH₃ CF₃ n-butyl n-butyl 4-F O CH₂ 921 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2,4-2F O CH₂ 922 CONHSO₂CH₃ CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 923 5-tetrazolyl CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 924 5-tetrazolyl CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 925 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 926 5-tetrazolyl CF₃ n-butyl n-butyl 2-F O CH₂ 927 5-tetrazolyl CF₃ n-butyl n-butyl 4-F O CH₂ 928 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2F O CH₂ 929 5-tetrazolyl CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 930 5-tetrazolyl CF₃ n-butyl n-butyl 2-CH₃ O CH₂ 931 5-tetrazolyl CF₃ n-butyl n-butyl 4-CH₃ O CH₂ 932 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2CH₃ O CH₂ 933 5-tetrazolyl CF₃ n-butyl n-butyl 2-F O CH₂ 934 5-tetrazolyl CF₃ n-butyl n-butyl 4-F O CH₂ 935 5-tetrazolyl CF₃ n-butyl n-butyl 2,4-2F O CH₂ 936 5-tetrazolyl CF₃ n-butyl n-butyl 2-F-4-CH₃ O CH₂ 937 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 938 COOCH₂CH₃ CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 939 COOCH₂CH₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 940 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-F O CH₂ 941 COOCH₂CH₃ CF₃ isobutyl isobutyl 4-F O CH₂ 942 COOCH₂CH₃ CF₃ isobutyl isobutyl 2,4-2F O CH₂ 943 COOCH₂CH₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 944 COOH CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 945 COOH CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 946 COOH CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 947 COOH CF₃ isobutyl isobutyl 2-F O CH₂ 948 COOH CF₃ isobutyl isobutyl 4-F O CH₂ 949 COOH CF₃ isobutyl isobutyl 2,4-2F O CH₂ 950 COOH CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 951 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 952 CONHSO₂CH₃ CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 953 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 954 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-F O CH₂ 955 CONHSO₂CH₃ CF₃ isobutyl isobutyl 4-F O CH₂ 956 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2,4-2F O CH₂ 957 CONHSO₂CH₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 958 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 959 CONHSO₂CF₃ CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 960 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 961 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-F O CH₂ 962 CONHSO₂CF₃ CF₃ isobutyl isobutyl 4-F O CH₂ 963 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2,4-2F O CH₂ 964 CONHSO₂CF₃ CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 965 5-tetrazolyl CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 966 5-tetrazolyl CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 967 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 968 5-tetrazolyl CF₃ isobutyl isobutyl 2-F O CH₂ 969 5-tetrazolyl CF₃ isobutyl isobutyl 4-F O CH₂ 970 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2F O CH₂ 971 5-tetrazolyl CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 972 5-tetrazolyl CF₃ isobutyl isobutyl 2-CH₃ O CH₂ 973 5-tetrazolyl CF₃ isobutyl isobutyl 4-CH₃ O CH₂ 974 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2CH₃ O CH₂ 975 5-tetrazolyl CF₃ isobutyl isobutyl 2-F O CH₂ 976 5-tetrazolyl CF₃ isobutyl isobutyl 4-F O CH₂ 977 5-tetrazolyl CF₃ isobutyl isobutyl 2,4-2F O CH₂ 978 5-tetrazolyl CF₃ isobutyl isobutyl 2-F-4-CH₃ O CH₂ 979 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 980 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 981 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 982 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-F O CH₂ 983 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 4-F O CH₂ 984 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 985 COOCH₂CH₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 986 COOH CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 987 COOH CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 988 COOH CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 989 COOH CF₃ cyclohexyl isobutyl 2-F O CH₂ 990 COOH CF₃ cyclohexyl isobutyl 4-F O CH₂ 991 COOH CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 992 COOH CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 993 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 994 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 995 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 996 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-F O CH₂ 997 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 4-F O CH₂ 998 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 999 CONHSO₂CH₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 1000 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 1001 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 1002 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 1003 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-F O CH₂ 1004 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 4-F O CH₂ 1005 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 1006 CONHSO₂CF₃ CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 1007 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 1008 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 1009 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 1010 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F O CH₂ 1011 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-F O CH₂ 1012 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 1013 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F-4-CH₃ O CH₂ 1014 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-CH₃ O CH₂ 1015 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-CH₃ O CH₂ 1016 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2CH₃ O CH₂ 1017 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F O CH₂ 1018 5-tetrazolyl CF₃ cyclohexyl isobutyl 4-F O CH₂ 1019 5-tetrazolyl CF₃ cyclohexyl isobutyl 2,4-2F O CH₂ 1020 5-tetrazolyl CF₃ cyclohexyl isobutyl 2-F-4CH₃ O CH₂ 1021 COOCH₂CH₃ CH₃ n-butyl n-butyl 2-Cl O NH 1022 COOCH₂CH₃ CH₃ n-butyl n-butyl 3-Cl O NH 1023 COOCH₂CH₃ CH₃ n-butyl n-butyl 4-Cl O NH 1024 COOCH₂CH₃ CH₃ n-butyl n-butyl 3-CF₃4-Cl O NH 1025 COOCH₂CH₃ CH₃ n-butyl n-butyl H S NH 1026 COOCH₂CH₃ CH₃ n-butyl n-butyl 3-CH₃ O NH 1027 COOH CH₃ n-butyl n-butyl 2-Cl O NH 1028 COOH CH₃ n-butyl n-butyl 3-Cl O NH 1029 COOH CH₃ n-butyl n-butyl 4-Cl O NH 1030 COOH CH₃ n-butyl n-butyl 3-CF₃4-Cl O NH 1031 COOH CH₃ n-butyl n-butyl H S NH 1032 COOH CH₃ n-butyl n-butyl 3-CH₃ O NH

The formula I compound of the invention can be prepared according to the following methods:

In the above reaction formula, the commercial halo nitroaromatic ketone compound 1 reacts with the substituted amino compound 2 to form the substituted amino nitroaromatic ketone compound 3 under the alkaline condition. Compound 3 reacts with wittingene reagent to form aromatic ethylene compound 4 under the alkaline condition. Compound 4 is reduced to amino compound 5 under the condition of reducing agent. Compound 5 reacts with compound 6 (isocyanate, isothiocyanate and chloroformate) to form formula I compound.

In the scheme:

L is selected from halogen, where L=F, Cl, Br and I; the definitions of the other groups are the same as before.

Base is selected from KOH, NaOH, Na₂CO₃, K₂CO₃, NaHCO₃, Et₃N, pyridine, MeONa, EtONa, NaH, potassium tert-butoxide or sodium tert-butoxide and so on.

The reaction is carried out in a suitable solvent, solvent is selected from THF, MeCN, PhMe, Xylene, Benzene, DMF, DMSO, acetone or methyl ethyl ketone and so on.

The reaction temperature may be between room temperature and the boiling point of the solvent, usually from 20 to 100° C.

The reaction time is from 30 minutes to 20 hours, usually from 1 to 10 hours.

The invention includes a formulation prepared by using the compound contained in the formula I as an active ingredient and other preparations. The preparation method of the formulation is as follows: dissolving the compound of the invention into a water-soluble organic solvent, a nonionic surfactant, a water-soluble lipid, various cyclodextrins, a fatty acid, a fatty acid ester, a phospholipid or their combined solvents to prepare a preparation solution; adding normal saline to get 1-20% carbohydrates. The organic solvent includes one or a combination of polyethylene glycol (PEG), ethanol, propylene glycol and the like.

The compound shown in formula I of the present invention, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, or a combination thereof, in the preparation of an inhibitor for inhibiting the activity of IDO-1 enzyme.

The compound shown in formula I of the present invention, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, or a combination thereof, in the preparation of an anti-cancer drug, a viral infectious agent, a depressant, an organ transplant rejection agent or an autoimmune enhancer.

The cancer referred to is colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, cervical cancer, renal cancer, leukemia, prostate cancer, pancreatic cancer or gastric cancer.

A pharmaceutical composition, any one or more compounds of formula I, its stereoisomer, cis-trans isomer, tautomer, pharmaceutically acceptable salts thereof and pharmaceutically acceptable carriers or diluents.

The compound of the present invention can be used as an active ingredient of an antitumor drug, and can be used alone or in combination with other antitumor drugs. The combination therapy referred to herein includes the use of at least one compound of the invention and a reactive derivative thereof in combination with one or more other anti-tumor agents to increase overall efficacy. The dose and time of administration in combination should be determined according to the most reasonable therapeutic effect obtained under different conditions.

The pharmaceutical agents contemplated include an effective dose of a compound of formula I. By “effective amount” herein is meant the amount of the compound required to produce a therapeutic effect for the subject being treated. The effective dose or dose can be varied by an experienced person depending on the recommendations of the situation. For example, the type of tumor treated is different, the usage of the drug is different; whether it is shared with other treatment methods such as other anti-tumor drugs, the dosage can be changed. Any application formulation form that can be made. If some of them have a basic or acidic compound and can form a non-toxic acid or salt, the form of the salt of the compound can be used. The carboxylic acid compound may form a usable salt with an alkali metal or an alkaline earth metal.

The compounds encompassed by the formula I in the invention are generally soluble in organic solvents, water-soluble solvents, organic solvents or a mixed solvent of a water-soluble solvent and water. The water-soluble solvent is preferably alcohol, polyethylene glycol, N-methyl-2-pyrrolidinone, DMA, DMF, DMSO, acetonitrile and their combination. The alcohol is preferably methanol, ethanol, isopropanol, glycerol or ethylene glycol. The compound of the present invention can be formulated into a preparation by mixing with usual formulation carriers. The compound is dissolved in a water-soluble organic solvent, an aprotic solvent, a water-soluble lipid, a cyclodextrin, a fatty acid, a phospholipid or a mixed solvent of these solvents to prepare a drug solution; and then adding physiological saline to obtain 1-20% carbohydrates, such as an aqueous solution of glucose. The formulations thus prepared are stable and are used in animals and clinical trials.

The product drug prepared by using the compound of the formula I as an active ingredient can be administered by oral or parenteral route, or can be administered by a drug pump in vivo and other methods. The non-intestinal route refers to subcutaneous intradermal, intramuscular, intravenous, intraarterial, intraatrial, synovial, sternal, intrathecal, traumatic site, intracranial injection or drip technology and so on. Professional person uses a conventional method to mix and mix and finally become the desired pharmaceutical dosage form. It may be a tablet, a capsule, an emulsion, a powder, a small needle for intravenous administration, a large infusion, a lyophilized powder, a dropping pill, a milk suspension, an aqueous suspension solution, an aqueous solution, a colloid, a colloidal solution, a sustained release preparation, a nano preparation or other forms of the dosage form are for animal or clinical use.

The compound of formula I of the invention is useful for the treatment or amelioration of cancer drugs for a certain tissue or organ. The cancers referred to include, but are not limited to, colon cancer, liver cancer, lymphoma, lung cancer, esophageal cancer, breast cancer, central nervous system tumor, melanoma, ovarian cancer, renal cancer, leukemia, prostate cancer or pancreatic cancer.

The invention has the advantages of having IDO-1 enzyme inhibitory activity and is expected to provide a novel therapeutic method and scheme for the related diseases caused by the IDO enzyme.

THE DETAILED DESCRIPTION OF THE INVENTION

The following examples are provided to assist in a comprehensive understanding of the claims and their equivalents, and are not intended to limit the present invention.

Example 1

To a 250 mL flask, 10.0 g of 3′-nitro-4′-chlorocetophenone and 100 mL of di-n-butylamine were added, and the mixture was heated at 100° C. for 20 hours. After reaction was completed by TLC monitoring, the reaction mixture was evaporated to dryness, and the residue was dissolved in ethyl acetate (300 mL) and washed with water (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate for 12 hr. The solvent was removed in vacuo. purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), the volume ratio is 1:6)) to obtain the compound 1-(4-(dibutylamino)-3-nitrophenyl)ethan-1-one, 11.3 g yellow solid.

¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.89 (t, J=7.5 Hz, 6H), 1.23-1.35 (m, 4H), 1.52-1.62 (m, 4H), 2.51 (s, 3H), 3.23 (t, J=7.2 Hz, 4H), 7.08 (dd, J=14.4, 3.9 Hz, 1H), 7.96 (dd, J=9.0, 2.1 Hz, 1H), 8.31 (dd, J=2.1 Hz, 1H).

Example 2

To a 250 mL flask, 9.9 g of sodium t-butoxide and 150 mL of tetrahydrofuran were added, and 23.0 g of ethyl 2-(diethoxyphosphoryl)acetate was added dropwise with stirring at a temperature of 0 to 5° C. After the dropwise addition completely, the mixture was stirred at room temperature for 0.5 hour, and the compound 1-(4-(dibutylamino)-3-nitrophenyl)ethan-1-one dissolved in 50 mL of tetrahydrofuran was added dropwise with stirring at a temperature of 20-30° C. After the dropwise addition completely, the mixture was stirred at room temperature for 12 hours. After reaction was completed by TLC monitoring, the reaction mixture was washed with a saturated aqueous solution of ammonium chloride (100 mL×3), and the organic phase was dried over anhydrous sodium sulfate for 12 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:10) to obtain the compound ethyl (E)-3-(4-(dibutylamino)-3-nitrophenyl)but-2-enoate, 6.3 g yellow solid.

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 0.87 (t, J=7.5 Hz, 6H), 1.17-1.34 (m, 7H), 1.48-1.62 (m, 4H), 2.51 (s, 3H), 3.16 (t, J=7.2 Hz, 4H), 4.18 (q, J=7.2 Hz, 2H), 6.14 (d, J=1.2 Hz, 1H), 7.53-7.54 (m, 2H), 7.87 (d, J=2.1 Hz, 1H).

Example 3

To a 250 mL flask, 2.7 g of compound ethyl (E)-3-(4-(dibutylamino)-3-nitrophenyl)but-2-enoate, 4.0 g of ammonium chloride, zinc powder 4.9 g, 100 mL of ethanol and 20 mL of water were added, the mixture was stirred at room temperature for 2 hours. After reaction was completed by TLC monitoring, the reaction mixture was filtered, and the solvent of filtrate was removed in vacuo. Purification of residues by silica gel column chromatography (eluent ethyl acetate and petroleum ether (boiling range: 60-90° C.), volume ratio: 1:10) to obtain the compound ethyl (E)-3-(3-amino-4-(dibutylamino)phenyl)but-2-enoate, 0.3 g reddish brown viscous liquid.

¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.87 (t, J=6.9 Hz, 6H), 1.10 (t, J=6.9 Hz, 3H), 1.23-1.30 (m, 4H), 1.33-1.43 (m, 4H), 2.16 (d, J=1.5 Hz, 3H), 2.86 (t, J=7.5 Mz, 4H), 4.03 (q, J=6.9 Hz, 2H), 6.08 (d, J=0.9 Hz, 1H), 6.56-6.60 (m, 2H), 6.96 (d, J=7.5 Hz, 1H).

Example 4

To a 100 mL flask, 0.3 g of compound ethyl (E)-3-(3-amino-4-(dibutylamino)phenyl)but-2-enoate and acetonitrile 50 mL were added, irradiated with UV light (wavelength: 365 nM) for 48 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:10) to obtain the compound ethyl (Z)-3-(3-amino-4-(dibutylamino)phenyl)but-2-enoate, 0.11 g reddish brown viscous liquid.

¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.87 (t, J=−6.9 Hz, 6H), 1.09 (t, J=6.9 Hz, 3H), 1.22-1.30 (m, 4H), 1.33-1.42 (m, 4H), 2.15 (d, J=1.5 Hz, 3H), 2.86 (t, J=7.5 Mz, 4H), 4.01 (q, J=6.9 Hz, 2H), 5.82 (d, J=0.9 Hz, 1H), 6.56-6.60 (m, 2H), 6.97 (d, J=7.5 Hz, 1H).

Example 5

To a 100 mL flask, 0.4 g of the compound ethyl (E)-3-(3-amino-4-(dibutylamino)phenyl)but-2-enoate, 0.16 g of p-toluene isocyanate and 30 mL of tetrahydrofuran were added. The mixture was stirred at room temperature for 8 hours. After reaction was completed by TLC monitoring, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range: 60-90° C.), volume ratio: 1:5) to obtain the compound ethyl (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoate (Compound 518), 0.12 g white solid.

¹H-NMR (300 MHz, CDCl₃) δ(ppm): 0.81 (t, J=6.9 Hz, 6H), 1.12-1.16 (m, 81), 1.30 (t, J=6.9 Hz, 3H), 2.35 (s, 3H), 2.72 (t, J=6.9 Hz, 4H), 4.18 (q, J=6.9 Hz, 2H), 6.18 (s, 1H), 6.45 (s, 1H), 7.08-7.26 (m, 5H), 8.22 (s, 1H), 8.45 (s, 1H).

Example 6

To a 100 mL flask, 0.3 g of the compound ethyl (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoate and acetonitrile 50 mL were added, irradiated with UV light (wavelength: 365 nM) for 48 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:6) to obtain the compound ethyl (Z)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoate (Compound 2), 0.10 g white solid.

Example 7

To a 100 mL flask, 100 g of compound ethyl (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido) phenyl)but-2-enoate, ethanol 50 mL and 3.0 g of sodium hydroxide were added. The mixture was stirred at room temperature for 12 hours. After reaction was completed by TLC monitoring, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (300 mL) and water (100 mL), and the mixture was adjusted to pH=3 with concentrated hydrochloric acid, and the organic phase was dried over anhydrous sodium sulfate for 12 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.) in a volume ratio of 1:2) to obtain the compound (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoic acid (Compound 525), 0.11 g white solid.

¹H-NMR (300 MHz, CDCl₃) δ (ppm): 0.81 (t. J=6.9 Hz, 6H), 1.13-1.17 (m, 8H), 2.35 (s, 31-H), 2.73 (t, J=6.9 Hz, 4H), 6.17 (s, 1H), 6.46 (s, 1H), 7.07-7.25 (m, 5H), 8.23 (s, 1H), 8.46 (s, 1H), 12.05 (s, 1H). MS (ESI), m/z (%): 438.32 [M+H]⁺.

Example 8

To a 100 mL flask, 0.3 g of compound (E)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoic acid and 50 mL of acetonitrile were added, irradiated with UV light (wavelength: 365 nM) for 48 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:2) to obtain compound (Z)-3-(4-(dibutylamino)-3-(3-(p-tolyl)ureido)phenyl)but-2-enoic acid (Compound 9), 0.16 g white solid.

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 0.85 (t, J=6.9 Hz, 6H), 1.19-1.31 (m, 8H), 2.26 (s, 3H), 2.50 (s, 3H), 2.83-2.88 (m, 4H), 5.81 (s, 1H), 7.03-7.12 (m, 3H), 7.33-7.37 (m, 2H), 8.04 (s, 1H), 8.82-8.36 (m, 1H), 8.36 (s, 1H), 9.35 (s, 1H). MS (ESI), m/z (%): 438.32 [M+H]⁺.

Example 9

To a 100 mL flask, 0.5 g of the compound ethyl (E)-3-(3-amino-4-(diisobutylamino)phenyl)but-2-enoate (preparation method is the same as in Example 1, Example 2 and Example 3), 3 g of 2,4-difluorophenyl isocyanate and 30 mL of tetrahydrofuran were added. The mixture was stirred at room temperature for 4 hours. After reaction was completed by TLC monitoring, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range: 60-90° C.), volume ratio: 1:5) to obtain the compound ethyl (E)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl) but-2-enoate (Compound 564), 0.16 g white solid.

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.83 (d, J=6.0 Hz, 12H), 1.24 (t, J=6.0 Hz, 3H), 1.69-1.72 (m, 2H), 2.49 (s, 3H), 2.79 (d, J=12.0 Hz, 4H), 4.13 (q, J=6.0 Hz, 2H), 6.09 (s, 1H), 7.03-7.05 (m, 1H), 7.19-7.23 (m, 2H), 7.29-7.31 (t, J=6 Hz, 1H), 7.98-8.01 (m, 1H), 8.05 (d, J=6.0 Hz, 1H), 8.09 (s, 1H), 9.33 (s, 1H). MS (ESI), m/z (%): 488.32[M+H]⁺.

Example 10

To a 100 mL flask, 0.3 g of the compound ethyl (E)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl) but-2-enoate, ethanol 50 mL and sodium hydroxide 3.0 g were added. The mixture was stirred at room temperature for 12 hours. After reaction was completed by TLC monitoring, the solvent was removed in vacuo, and the residue was dissolved in ethyl acetate (300 mL) and water (100 mL), and the mixture was adjusted to pH=3 with concentrated hydrochloric acid, and the organic phase was dried over anhydrous sodium sulfate for 12 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:2) to obtain the compound (E)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)but-2-enoic acid (Compound 571), 0.15 g white solid.

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 9.31 (s, 1H), 8.08 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.98-8.03 (m, 1H), 7.29-7.31 (t, J=6 Hz, 1H), 7.19-7.24 (m, 2H), 7.01-7.06 (m, 1H), 6.05 (s, 1H), 2.86-2.90 (m, 4H), 2.48 (s, 3H), 1.69-1.72 (m, 2H), 0.82 (d, J=6.0 Hz, 12H). MS (ESI), m/z (%): 460.27[M+H]⁺.

Example 11

To a 100 mL flask, 0.1 g of compound (E)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)but-2-enoic acid and 50 mL of acetonitrile, irradiated with UV light (wavelength: 365 nM) for 48 hours, the solvent was removed in vacuo. Purification of residues by silica gel column chromatography (eluents are ethyl acetate and petroleum ether (boiling range 60-90° C.), volume ratio 1:2) to obtain the compound (Z)-3-(3-(3-(2,4-difluorophenyl)ureido)-4-(diisobutylamino)phenyl)but-2-enoic acid (Compound 55), 0.03 g white solid.

¹H-NMR (600 MHz, DMSO-d₆) δ11.88 (s, 1H), 9.28 (s, 1H), 8.05 (s, 1H), 7.94 (td, J=9.1, 6.5 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.34-7.24 (m, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.87 (dd, J=8.2, 1.6 Hz, 1H), 5.84 (s, 1H), 2.70 (d, J=6.8 Hz, 4H), 2.09 (s, 3H), 1.71-1.66 (m, 2H), 0.85 (d, J=6.0 Hz, 12H). MS (ESI), m/z (%): 460.28[M+H]⁺.

Partial Compound Nuclear Magnetic Resonance Data:

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.45-1.17 (m, 8H), 2.50 (s, 3H), 2.87 (m, 4H), 5.86 (s, 1H), 6.85-7.32 (m, 4H), 8.05-8.00 (m, 1H), 8.25-8.32 (m, 1H), 8.66 (s, 1H), 9.40 (s, 1H). MS (ESI), m/z (%): 460.29 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.85 (t, J=6.0 Hz, 6H), 1.17-1.37 (m, 8H), 2.27 (s, 3H), 2.50 (s, 3H), 2.86-2.90 (m, 4H), 5.85 (s, 1H), 6.83 (d, J=0.6 Hz, 1H), 6.95 (d, J=0.6 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 7.16 (dd, J=4.2, 1.2 Hz, 1H), 7.88-7.94 (m, 1H), 8.33 (s, 1H), 8.63 (s, 1H), 9.28 (s, 1H). MS (ESI), m/z (%): 456.32[M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.21 (s, 1H), 9.22 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.86 (t, J=8.5 Hz, 1H), 7.45 (d, J=15.8 Hz, 1H), 7.28 (d, J=9.6 Hz, 1H), 7.16 (d, J=8.4 Hz, 1H), 7.05 (d, J=12.2 Hz, 1H), 6.92 (d, J=8.0 Hz, 1H), 5.89 (s, 1H), 2.80 (d, J=6.9 Hz, 4H), 2.45 (d, J=0.7 Hz, 3H), 2.21 (s, 3H), 1.71 (dt, J=13.3, 6.7 Hz, 2H), 0.82 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 438.30[M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ11.88 (s, OH), 9.28 (s, OH), 8.05 (s, 1H), 7.94 (td, J=9.1, 6.5 Hz, 1H), 7.78 (d, J=1.7 Hz, 1H), 7.34-7.24 (m, 1H), 7.13 (d, J=8.3 Hz, 1H), 7.04 (t, J=8.0 Hz, 1H), 6.87 (dd, J=8.2, 1.6 Hz, 1H), 5.84 (s, 1H), 2.70 (d, J=6.8 Hz, 4H), 2.09 (s, 3H), 1.71-1.66 (m, 2H), 0.85 (t, J=8.0 Hz, 12H). MS (ESI), m/z (%): 460.28[M+H]⁺. White solid.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 9.28 (s, 1H), 8.63 (s, 1H), 8.33 (s, 1H), 7.88-7.94 (m, 1H), 7.16 (dd, J=4.2, 1.2 Hz, 1H), 7.06 (d, J=1.2 Hz, 1H), 6.95 (d, J=0.6 Hz, 1H), 6.83 (d, J=0.6 Hz, 1H), 5.85 (s, 1H), 2.86-2.90 (m, 4H), 2.48 (s, 3H), 2.10 (s, 3H), 1.63-1.71 (m, 2H), 0.82 (d, J=6.0 Hz, 12H). MS (ESI), m/z (%): 456.29[M+H]⁺. White solid.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 0.85 (t, J=−6.9 Hz, 6H), 1.27-1.30 (m, 11H), 2.53 (s, 3H), 2.87-2.89 (m, 4H), 4.13 (q, J=6.9 Hz, 2H), 6.08 (s, 1H), 7.13-7.17 (m, 2H), 7.50 (d, J=9.3 Hz, 1H), 7.70 (d, J=9.3 Hz, 1H), 8.01 (s, 1H), 8.35 (s, 1H), 8.39 (s, 1H), 9.88 (s, 1H). MS (ESI), m/z (%): 488.55[M+H]⁺. White solid.

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 0.84 (t, J=6.9 Hz, 6H), 1.20-1.30 (m, 11H), 2.30 (s, 3H), 2.52 (s, 3H), 2.86-2.88 (m, 4H), 4.12 (q, J=6.9 Hz, 2H), 6.07 (s, 1H), 6.87-6.96 (m, 3H), 7.09 (s, 1H), 7.95-8.01 (m, 1H), 8.35 (s, 1H), 8.61 (s, 111), 9.21 (s, 1H). MS (ESI), m/z (%): 484.36[M+H]⁺. White solid.

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 0.85 (t, J=6.9 Hz, 6H), 1.19-1.34 (m, 8H), 2.49 (s, 3H), 2.86-2.91 (m, 4H), 6.05 (s, 1H), 6.91 (t, J=8.7 Hz, 3H), 7.00-7.12 (m, 3H), 8.10-8.19 (m, 1H), 8.32 (s, 1H), 8.26 (s, 1H), 8.63 (s, 1H), 9.32 (s, 1H). MS (ESI), m/z (%): 460.29[M+H]⁺. White solid.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.20-1.30 (m, 8H), 1.80 (s, 3H), 2.43 (s, 3H), 2.84-2.89 (m, 4H), 6.05 (s, 1H), 6.86-6.94 (m, 2H), 7.03-7.11 (m, 2H), 7.95-8.00 (m, 1H), 8.29 (s, 1H), 8.59 (s, 1H), 9.19 (s, 1H). MS (ESI), m/z (%): 456.32 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ(ppm): 0.83 (d, J=6.0 Hz, 12H), 1.24 (t, J=6.0 Hz, 3H), 1.69-1.72 (m, 2H), 2.49 (s, 3H), 2.79 (d, J=12.0 Hz, 4H), 4.13 (q, J=6.0 Hz, 2H), 6.09 (s, 1H), 7.03-7.05 (m, 1H), 7.19-7.23 (m, 2H), 7.29-7.31 (t, =6 Hz, 1H), 7.98-8.01 (m, 1H), 8.05 (d, J=6.0 Hz, 1H), 8.09 (s, 1H), 9.33 (s, 1H). MS (ESI), m/z (%): 488.32[M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 9.31 (s, 1H), 8.08 (s, 1H), 8.05 (d, J=6.0 Hz, 1H), 7.98-8.03 (m, 1H), 7.29-7.31 (t, J=6 Hz, 1H), 7.19-7.24 (m, 2H), 7.01-7.06 (m, 1H), 6.05 (s, 1H), 2.86-2.90 (m, 4H), 2.48 (s, 3H), 1.69-1.72 (m, 2H), 0.82 (d, J=6.0 Hz, 12H). MS (ESI), m/z (%): 460.27[M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ(ppm): 12.11 (s, 1H), 9.23 (s, 1H), 8.07 (s, 1H), 8.02 (s, 11-), 7.86 (t, J=8.5 Hz, 1H), 7.19 (s, 2H), 7.06 (d, J=12.2 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.06 (d, J=1.1 Hz, 11H), 2.77 (d, J=6.9 Hz, 4H), 2.46 (d, J=0.7 Hz, 3H), 2.27 (s, 3H), 1.70 (dt, J=13.4, 6.7 Hz, 2H), 0.83 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 456.30[M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.80 (t, J=6.0 Hz, 6H), 1.14-1.25 (m, 11H), 2.48 (s, 3H), 2.73 (t, J=6.0 Hz, 4H), 3.83 (s, 2H), 4.13 (q, J=6.0 Hz, 2H), 6.08 (s, 1H), 7.22-7.25 (m, 4H), 7.37-7.40 (m, 1H), 7.46-7.48 (m, 1H), 8.40 (s, 1H), 8.90 (s, 1H). MS (ESI), m/z (%): 469.34 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ(ppm): 0.80 (t, J=6.0 Hz, 6H), 1.13-1.23 (m, 8H), 2.45 (s, 3H), 2.71 (t, J=6.0 Hz, 4H), 3.83 (s, 2H), 6.05 (s, 1H), 7.22-7.27 (m, 4H), 7.37-7.40 (m, 1H), 7.46-7.48 (m, 1H), 8.39 (s, 1H), 8.89 (s, 1H), 12.18 (s, 1H). MS (ESI), m/z (%): 441.15[M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.13 (s, 1H), 8.44 (s, 1H), 8.36 (s, 1H), 7.27-7.12 (m, 6H), 6.00 (s, 1H), 3.74 (s, 2H), 2.50 (s, 2H), 2.48 (s, 2H), 2.41 (s, 3H), 2.22 (s, 31-), 1.51 (dt, J=13.1, 6.4 Hz, 2H), 0.69 (d, J=6.5 Hz, 12H). MS (ESI), m/z (%): 437.31 [M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 8.59 (s, 1H), 8.07 (d, J=1.9 Hz, 1H), 7.74 (s, 1H), 7.28 (d, J=8.0 Hz, 1H), 7.13 (dt, J=8.5, 5.3 Hz, 2H), 6.98 (s, 1H), 6.93 (d, J 8.4 Hz, 1H), 6.00 (s, 1H), 2.64 (d, J=6.9 Hz, 4H), 2.42 (s, 3H), 2.21 (s, 3H), 2.15 (s, 3H), 1.60 (dd, J=13.0, 6.4 Hz, 2H), 0.78 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 452.32 [M+H]⁺. White solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 12.17 (s, 1H), 8.80 (d, J=15.8 Hz, 1H), 8.33 (s, 1H), 7.43 (t, J=7.4 I-Hz, 1H), 7.36 (dd, J=13.4, 6.2 Hz, 1H), 7.28 (s, 2H), 7.20 (dd, J=12.6, 5.3 Hz, 2H), 6.05 (s, 1H), 3.85-3.77 (m, 2H), 2.61 (t, J=12.7 Hz, 4H), 2.45 (s, 3H), 1.62 (dt, J=12.0, 6.0 Hz, 2H), 0.79 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 441.27 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.16 (s, 1H), 8.72 (d, J=21.6 Hz, 1H), 8.30 (s, 1H), 7.38 (s, 2H), 7.31-7.13 (m, 4H), 6.04 (s, 1H), 3.74 (d, J=18.0 Hz, 2H), 2.59 (t, J=13.6 Hz, 4H), 2.45 (s, 3H), 1.59 (d, J=5.8 Hz, 2H), 0.77 (d, J=5.9 Hz, 12H). MS (ESI), m/z (%): 441.27 [M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 12.12 (s, 1H), 9.42 (s, 1H), 8.20 (d, J=2.1 Hz, 1H), 7.86 (s, 1H), 7.33 (d, J=8.4 Hz, 2H), 7.13 (dt, J=8.4, 5.3 Hz, 2H), 7.06 (d, J=8.3 Hz, 2H), 6.03 (d, J=1.2 Hz, 11H), 2.77 (d, J=5.3 Hz, 2H), 2.53 (t, J=10.7 Hz, 1H), 2.44 (d, J=1.0 Hz, 3H), 2.21 (s, 3H), 1.89-1.79 (m, 2H), 1.64 (d, J=11.7 Hz, 2H), 1.46 (d, J=10.7 Hz, 1H), 1.31 (ddd, J=22.4, 14.4, 7.9 Hz, 2H), 1.14 (ddd, J=30.5, 21.7, 12.0 Hz, 4H), 0.78 (d, J=6.6 Hz, 6H). MS (ESI), m/z (%): 464.33 [M+H]⁺. White solid.

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 0.86 (t, J=6.9 Hz, 61H), 1.19-1.37 (m, 11H), 2.53 (s, 3H), 2.89 (t, J=6.6 Hz, 4H), 4.14 (q, J=6.9 Hz, 2H), 6.09 (d, J=1.2 Hz, 1H), 6.90-6.94 (m, 1H), 7.07-7.15 (m, 2H), 7.19-7.28 (m, 2H), 7.72 (d, J=1.8 Hz, 1H), 8.33 (s, 1H), 8.37 (d, J=1.5 Hz, 1H), 9.57 (s, 1H). MS (ESI), m/z (%): 487.30[M+H]⁻. White solid.

Compound 1022: R² is an ethyl ester group, and the olefinic bond is trans, and the specific structure is as follows:

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.25-1.35 (m, 11H), 2.50 (s, 3H), 2.89 (m, 4H), 4.09-4.16 (m, 2H), 6.06 (s, 1H), 6.98-7.03 (m, 3H), 7.22-7.27 (m, 1H), 7.35-7.37 (m, 1H), 8.00 (d, J=8.1 Hz, 1H), 8.26 (s, 1H), 8.68 (s, 1H), 8.96 (s, 1H). MS (ESI), m/z (%): 487.29[M+H]⁺. White solid.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.18-1.33 (m, 11H), 2.53 (s, 3H), 2.86-2.92 (m, 4H), 4.13 (q, J=6.9 Hz, 2H), 7.07-7.15 (m, 2H), 7.23 (d, J=−9.0 Hz, 2H), 7.50 (d, J=9.0 Hz, 2H), 8.32 (s, 1H), 8.38 (s, 1H), 9.53 (s, 1H). MS (ESI), m/z (%): 487.29[M+H]⁺. White solid.

Compound 1024: R² is an ethyl ester group, and the olefinic bond is trans, and the specific structure is as follows:

¹H-NMR (300 MHz, DMSO-d₆) δ(ppm): 0.85 (t, J=6.9 Hz, 6H), 1.18-1.32 (m, 11H), 2.51 (s, 3H), 2.87-2.89 (m, 4H), 4.12 (q, J=6.9 Hz, 2H), 6.07 (s, 1H), 6.91-6.93 (m, 1H), 7.07-7.17 (m, 311), 8.12-8.14 (m, 1H), 8.33 (s, 1H), 8.36 (s, 1H), 9.31 (s, 1H). MS (ESI), m/z (%): 555.34[M+H]⁺. White solid.

R² is an ethyl ester group, and the olefinic bond is trans, and the specific structure is as follows:

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.79 (t, J=6.0 Hz, 6H), 1.15 (q, J=6.0 Hz, 4H), 1.23-1.27 (m, 7H), 2.50 (s, 3H), 2.82 (t, J=6.0 Hz, 4H), 3.83 (s, 2H), 4.14 (q, J=6.0, 2H), 6.08 (s, 1H), 7.16 (d, J=12 Hz, 1H), 7.22 (t, J=12 Hz, 1H), 7.34 (d, J=6.0 Hz, 1H), 7.39 (dd, J=12.0, 6.0 Hz, 2H), 7.48 (d, J=6.0 Hz, 2H), 8.45 (s, 1H), 8.97 (s, 1H), 10.37 (s, 1H). MS (ESI), m/z (%): 468.31 [M+H]⁺. White solid.

R² is an ethyl ester group, and the olefinic bond is trans, and the specific structure is as follows:

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.81 (t, J=6.0 Hz, 6H), 1.21-1.29 (m, 11H), 2.29 (s, 3H), 2.51 (s, 3H), 2.90 (t, J=6.0 Hz, 41-), 4.15 (q, J=6.0 Hz, 4H), 6.11 (s, 1H), 6.80 (d, J=6.0 Hz, 1H), 7.15-7.25 (m, 4H), 7.36 (s, 1H), 8.35 (s, 1H), 8.39 (d, J=6.0 Hz 1H), 9.49 (s, 1H). MS (ESI), m/z (%): 466.36[M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.83 (t, J=6.0 Hz, 6H), 1.13-1.33 (m, 8H), 2.50 (s, 3H), 2.86-2.92 (m, 4H), 6.10 (s, 1H), 7.07-7.09 (m, 1H), 7.13-7.22 (m, 1H), 7.29-7.32 (m, 2H), 7.47 (d, J=12 Hz, 1H), 7.97 (s, 1H), 8.21 (s, 1H), 8.75 (s, 1H), 9.18 (s, 1H). MS (ESI), m/z (%): 459.27 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.85 (t, J=6.0 Hz, 6H), 1.21-1.31 (m, 8H), 2.50 (s, 3H), 2.92 (m, 4H), 4.09-4.16 (m, 2H), 6.10 (s, 1H), 7.02-7.03 (m, 1H), 7.27-7.33 (m, 3H), 7.76 (m, 1H), 8.01 (d, J=7.8 Hz, 1H), 8.32 (s, 1H), 8.47 (s, 1H), 9.84 (s, 1H). MS (ESI), m/z (%): 459.29[M+H]⁺. White solid.

¹H-NMR (300 MHz, DMSO-d₆) δ (ppm): 0.85 (t, J=6.9 Hz, 6H), 1.24-1.30 (m, 8H), 2.56 (s, 3H), 2.87-2.90 (m, 4H), 6.05 (s, 1H), 7.12-7.16 (m, 2H), 7.46-7.50 (m, 1H), 7.71 (d, J=8.1 Hz, 1H), 8.35-8.38 (m, 2H), 9.85 (s, 1H). MS (ESI), m/z (%): 527.29[M+H]⁺. White solid.

The olefinic bond is trans, Y is S substituted, and R is hydrogen. The specific structure is as follows:

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 0.80 (t, J=6.0 Hz, 6H), 1.16 (q, J=6.0 Hz, 4H), 1.22-1.28 (m, 4H), 2.51 (s, 3H), 2.80 (t, J=6.0 Hz, 4H), 3.85 (s, 2H), 6.09 (s, —1H), 7.17 (d, J-=12 Hz, 1H), 7.23 (t, J=12 Hz, 1H), 7.33 (d, J=6.0 Hz, 1H), 7.39 (dd, J=12.0, 6.0 Hz, 2H), 7.47 (d, J=6.0 Hz, 2H), 8.46 (s, 1H), 8.97 (s, 1H), 8.97 (s, 1H), 10.37 (s, 1H), 12.03 (s, 1H). MS (ESI), m/z (%): 440.27[M+H]⁺. White solid.

¹H-NMR (600 MHz, CDCl₃) δ (ppm): 8.37 (d, J=1.8 Hz, 1H), 8.13 (s, 1H), 7.60 (d, J=2.4 Hz, 1H), 7.38 (d, J=8.7 Hz, 1H), 7.27 (dd, J=9.5, 3.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.12 (dd, J=8.3, 2.0 Hz, 1H), 6.48 (s, 1H), 5.64 (s, 1H), 2.62 (d, J=7.2 Hz, 4H), 2.46 (s, 3H), 1.73 (dp, J=13.4, 6.7 Hz, 2H), 0.90 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 474.31[M+H]⁺. White solid.

¹H-NMR (600 MHz, CDCl₃) δ(ppm): 8.39 (d, J=1.8 Hz, 1H), 8.15 (s, 1H), 7.66 (d, J=9.8 Hz, 2H), 7.46 (t, J=7.8 Hz, 1H), 7.36 (d, J=7.7 Hz, 1H), 7.19 (d, J=8.3 Hz, 1H), 7.12 (dd, J=8.3, 2.0 Hz, 1H), 6.54 (s, 1H), 5.65 (s, 1H), 2.62 (d, J=7.2 Hz, 4H), 2.46 (s, 3H), 1.83-1.65 (m, 2H), 0.90 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 473.29[M+H]⁺. White solid.

¹H-NMR (600 MHz, CDCl₃) δ (ppm): 8.38 (d, J=1.7 Hz, 1H), 8.17 (s, 1H), 7.66-7.48 (m, 4H), 7.19 (d, J 8.4 Hz, 1H), 7.13 (dd, J=8.3, 1.8 Hz, 1H), 6.67 (s, 1H), 5.65 (s, 1H), 2.63 (d, J=7.2 Hz, 4H), 2.46 (s, 2H), 1.75 (dd, J=13.4, 6.7 Hz, 2H), 0.91 (d, J=6.5 Hz, 12H). MS (ESI), m/z (%): 473.23 [M+H]⁺. White solid.

¹H-NMR (600 MHz, CDCl₃) δ(ppm): 8.43 (s, 1H), 8.03 (s, 1H), 7.29-7.17 (m, 2H), 7.14 (d, J=8.5 Hz, 2H), 7.09 (d, J=8.3 Hz, 1H), 6.97 (d, J=7.5 Hz, 1H), 6.40 (s, 1H), 5.64 (s, 1H), 2.57 (d, J=7.2 Hz, 4H), 2.46 (s, 3H), 2.35 (s, 3H), 1.68 (m, 2H), 0.83 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 419.35[M+H]⁺. White solid.

¹H-NMR (600 MHz, CDCl₃) δ(ppm): 8.39 (d, J=1.8 Hz, 1H), 8.12 (s, 1H), 7.46 (s, 1H), 7.27 (d, J=5.6 Hz, 2H), 7.17 (d, J=8.3 Hz, 1H), 7.11 (d, J=7.8 Hz, 2H), 6.41 (s, 1H), 5.64 (s, 1H), 2.60 (d, J=7.2 Hz, 4H), 2.46 (s, 3H), 1.72 (m, 2H), 0.88 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 440.27[M+H]⁺. White solid.

¹H-NMR (600 MHz, CDCl₃) δ (ppm): 8.39 (s, 1H), 8.09 (s, 1H), 7.32 (dd, J=25.8, 8.0 Hz, 4H), 7.17 (d, J=8.3 Hz, 1H), 7.11 (d, J=8.3 Hz, 1H), 6.40 (s, 1H), 5.64 (s, 1H), 2.59 (d, J=6.9 Hz, 4H), 2.46 (s, 3H), 1.81-1.64 (m, 2H), 0.88 (d, J=6.3 Hz, 12H). MS (ESI), m/z (%): 440.27[M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ (ppm): 12.13 (s, 1H), 9.42 (s, 1H), 8.16 (d, J=1.9 Hz, 1H), 7.80 (s, 1H), 7.35 (s, 1H), 7.21 (ddd, J=22.3, 20.0, 7.9 Hz, 4H), 6.80 (d, J=7.4 Hz, 1H), 6.07 (s, 1H), 2.74 (d, J=6.9 Hz, 4H), 2.48 (s, 3H), 2.29 (s, 3H), 1.68 m, 2H), 0.90-0.78 (m, 12H). MS (ESI), m/z (%): 438.30[M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 8.66 (s, 1H), 8.24 (s, 1H), 7.33 (dd, J=8.3, 5.7 Hz, 2H), 7.24-7.18 (m, 2H), 7.13 (t, J=8.9 Hz, 2H), 5.91 (d, J=1.1 Hz, 1H), 3.71 (s, 2H), 2.54 (t, J=10.5 Hz, 4H), 2.39 (d, J=0.9 Hz, 3H), 1.55 (dt, J=13.2, 6.4 Hz, 2H), 1.42 (s, 9H), 0.73 (t, J=6.6 Hz, 12H). MS (ESI), m/z (%): 497.39 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 8.71 (d, J=34.7 Hz, 1H), 8.31 (s, 1H), 7.38-7.31 (m, 4H), 7.28 (t, J=6.4 Hz, 1H), 7.24 (d, J=8.3 Hz, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.73 (d, J=22.4 Hz, 2H), 2.64-2.53 (m, 4H), 2.43 (d, J=1.0 Hz, 3H), 1.58 (dt, J=13.3, 6.5 Hz, 2H), 1.46 (s, 9H), 0.76 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 479.37 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) 8.79 (d, J=17.0 Hz, 1H), 8.30 (s, 1H), 7.43 (t, J=7.5 Hz, 1H), 7.35 (dd, J=13.8, 7.1 Hz, 1H), 7.27 (s, 2H), 7.20 (dd, J=12.8, 5.9 Hz, 2H), 5.95 (d, J=1.2 Hz, 1H), 3.78 (d, J=25.1 Hz, 2H), 2.59 (dd, J=35.8, 6.6 Hz, 4H), 2.44 (d, J=1.1 Hz, 3H), 1.65-1.56 (nm, 2H), 1.46 (s, 9H), 0.80 (t, J=6.2 Hz, 12H). MS (ESI), m/z (%): 497.39 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 8.48 (s, 1H), 8.38 (s, 1H), 7.32-7.08 (m, 6H), 5.96 (s, 1H), 3.76 (d, J=21.2 Hz, 2H), 2.53 (t, J=9.0 Hz, 4H), 2.44 (s, 3H), 2.25 (d, J=12.5 Hz, 3H), 1.56 (td, J=13.1, 6.5 Hz, 2H), 1.46 (s, 9H), 0.73 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 493.41 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.14 (s, 1H), 8.71 (d, J=28.8 Hz, 1H), 8.33 (s, 1H), 7.39-7.18 (m, 7H), 6.04 (s, 1H), 3.73 (d, J=19.9 Hz, 2H), 2.56 (dd, J=29.0, 6.8 Hz, 4H), 2.45 (s, 3H), 1.67-1.48 (m, 2H), 0.77 (t, J=9.6 Hz, 12H). MS (ESI), m/z (%): 423.28 [M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.69 (s, 1H), 8.06 (d, J=1.7 Hz, 1H), 7.82 (s, 1H), 7.48 (d, J=12.0 Hz, 1H), 7.28 (dd, J=15.2, 8.1 Hz, 1H), 7.15 (ddd, J=16.2, 14.1, 8.2 Hz, 3H), 6.80-6.72 (m, 1H), 5.94 (s, 1H), 2.69 (t, J=10.2 Hz, 4H), 2.42 (s, 3H), 1.64 (dt, J=13.2, 6.5 Hz, 2H), 1.43 (s, 9H), 0.80 (d, J=6.6 Hz, 12H). MS (ESI), m/z (%): 498.37 [M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 8.57 (d, J=22.5 Hz, 1H), 8.06 (d, J=2.0 Hz, 1H), 7.72 (d, J=18.3 Hz, 1H), 7.31 (dd, J=28.4, 9.0 Hz, 1H), 7.12 (dt, J=8.4, 5.3 Hz, 2H), 6.98 (s, 1H), 6.93 (d, J=8.1 Hz, 1H), 5.92 (d, J=1.2 Hz, 1H), 2.70-2.56 (m, 4H), 2.43-2.34 (m, 3H), 2.20 (d, J=8.3 Hz, 3H), 2.16 (d, J=8.7 Hz, 3H), 1.60 (td, J=13.2, 6.5 Hz, 2H), 1.47-1.33 (m, 9H), 0.85-0.71 (m, 12H). MS (ESI), m/z (%): 508.41 [M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.72 (s, 1H), 8.08 (d, J=2.0 Hz, 1H), 7.84 (s, 1H), 7.49 (d, J=12.0 Hz, 1H), 7.29-7.24 (m, 1H), 7.21-7.15 (m, 2H), 7.11 (d, J=7.9 Hz, 1H), 6.77-6.72 (m, 1H), 6.03 (d, J=1.1 Hz, 1H), 2.71 (d, J=6.9 Hz, 4H), 2.43 (s, 3H), 1.64 (dd, J=11.9, 5.4 Hz, 2H), 0.81 (t, J=6.2 Hz, 12H). MS (ESI), m/z (%): 442.29 [M+H]⁺. White solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 9.45 (s, 1H), 8.22 (d, J=2.2 Hz, 1H), 7.91 (s, 1H), 7.36 (dd, J=10.7, 5.5 Hz, 2H), 7.19 (d, J=8.4 Hz, 1H), 7.15 (dd, J=8.3, 2.2 Hz, 1H), 7.10 (d, J=8.3 Hz, 2H), 5.99 (d, J=1.2 Hz, 1H), 2.81 (d, J=5.0 Hz, 2H), 2.58 (dd, =23.5, 11.8 Hz, 1H), 2.47 (d, J=1.0 Hz, 3H), 2.25 (s, 3H), 1.87 (d, J=11.1 Hz, 2H), 1.69 (d, J=12.5 Hz, 2H), 1.51 (d, J=8.4 Hz, 1H), 1.48 (s, 9H), 1.33 (ddd, J=25.1, 12.5, 5.5 Hz, 2H), 1.29-1.21 (m, 4H), 0.83 (d, J=6.6 Hz, 6H). MS (ESI), m/z (%): 520.40 [M+H]⁺. White solid.

¹H-NMR (500 MHz, DMSO-d₆) δ 8.89 (s, 2H), 8.04 (td, J=9.1, 6.3 Hz, 1H), 7.68 (d, J=2.2 Hz, 1H), 7.36-7.19 (m, 2H), 7.02 (dd, J=11.4, 4.8 Hz, 1H), 6.87 (d, J=8.5 Hz, 1H), 5.95 (s, 1H), 3.19 (q, J=7.1 Hz, 2H), 2.43 (s, 3H), 1.44 (s, 9H), 1.22 (dd, J=9.1, 5.1 Hz, 3H). MS (ESI), m/z (%): 432.22 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 9.40 (s, 1H), 8.71 (s, 11H), 8.53 (s, 1H), 8.20-8.07 (m, 1H), 7.46 (dd, J=15.3, 8.8 Hz, 1H), 7.27 (s, 1H), 7.08-6.96 (m, 2H), 6.05 (s, 1H), 3.28 (d, J=57.3 Hz, 2H), 2.50 (s, 3H), 1.48 (s, 9H), 1.04 (t, J=6.9 Hz, 3H) MS (ESI), m/z (%): 432.23 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 11.88 (s, 1H), 8.63 (s, 1H), 8.21-8.03 (m, 2H), 7.61 (s, 1H), 7.38-7.22 (m, 2H), 7.00 (dt, J=10.3, 5.5 Hz, 1H), 6.66 (d, J=8.6 Hz, 1H), 6.01 (s, 1H), 3.14 (t, J=12.4 Hz, 2H), 2.46 (s, 3H), 1.22 (t, J=7.1 Hz, 3H). MS (ESI), m/z (%): 376.16 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.26 (s, 1H), 9.40 (s, 1H), 8.72 (s, 1H), 8.57 (s, 1H), 8.21-8.10 (m, 1H), 7.54 (d, J=16.3 Hz, 1H), 7.46 (dd, J=15.6, 7.7 Hz, 1H), 7.25-7.17 (m, 1H), 7.01 (ddd, J=22.5, 16.5, 9.2 Hz, 2H), 6.14 (s, 1H), 3.93 (s, 1H), 3.23 (s, 1H), 2.53-2.51 (m, 3H), 1.05 (t, J=7.1 Hz, 3H). MS (ESI), m/z (%): 376.16 [M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.37 (s, 1H), 8.66 (s, 1H), 8.49 (d, J=1.6 Hz, 1H), 8.11 (dd, J=9.2, 3.1 Hz, 1H), 7.50 (s, 1H), 7.40 (dd, J=9.0, 2.7 Hz, 1H), 7.23 (d, J=1.4 Hz, 1H), 7.03 (d, J=9.1 Hz, 1H), 6.95 (d, J=7.7 Hz, 1H), 6.00 (d, J=1.2 Hz, 1H), 3.81 (s, 2H), 3.04 (s, 2H), 2.46 (s, 3H), 1.44 (s, 9H), 0.79 (t, J=7.4 Hz, 3H). MS (ESI), m/z (%): 446.23 [M+H]⁺. White solid.

¹H-NMR (400 MHz, DMSO-d₆) δ 9.33 (s, 1H), 8.72 (s, 1H), 8.47 (d, J=2.0 Hz, 1H), 8.12 (td, J=9.3, 6.1 Hz, 11H), 7.69 (s, 1H), 7.27 (s, 1H), 7.03 (d, J=9.2 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 6.00 (d, J=1.2 Hz, 1H), 3.07 (s, 3H), 2.45 (d, J=1.1 Hz, 3H), 1.44 (s, 9H). MS (ESI), m/z (%): 418.22 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.63-11.42 (m, 1H), 9.24 (s, 1H), 8.83-8.55 (m, 2H), 8.36-8.14 (m, 1H), 7.98 (s, 1H), 7.25 (dd, J=33.2, 25.4 Hz, 2H), 6.88-6.81 (m, 2H), 6.21 (s, 1H), 4.02 (s, 1H), 3.20 (s, 1H), 2.65-2.59 (m, 3H), 1.64 (s, 2H), 0.92 (dd, J=14.9, 7.4 Hz, 3H). MS (ESI), m/z (%): 390.21 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 9.17-9.02 (m, 1H), 8.70 (d, J=46.5 Hz, 2H), 8.22 (dd, J=15.1, 9.1 Hz, 1H), 7.96 (s, 1H), 7.30 (s, 2H), 6.86-6.80 (m, 2H), 6.21 (s, 1H), 3.27 (d, J=5.4 Hz, 3H), 2.58 (s, 3H). MS (ESI), m/z (%): 362.26 [M+H]⁺. White solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.45 (s, 1H), 7.96 (s, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.21 (s, 1H), 7.14 (s, 1H), 7.11 (s, 3H), 6.41 (d, J=16.0 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 2.53 (d, J=7.2 Hz, 4H), 2.32 (s, 3H), 1.65 (dt, J=13.5, 6.7 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.79 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 452.34 [M+H]⁺. White solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 8.18 (s, 1H), 7.99 (td, J=9.2, 6.0 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.14 (s, 2H), 6.90-6.81 (m, 2H), 6.39 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 2.59 (d, J=7.3 Hz, 4H), 1.72 (dt, J=13.5, 6.8 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.88 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 474.33 [M+H]⁺. White solid.

¹H-NMR (400 MHz, CDCl₃) δ 8.43 (s, 1H), 8.14 (s, 1H), 7.86 (t, J=8.4 Hz, 1H), 7.63 (d, J=16.0 Hz, 1H), 7.13 (s, 2H), 6.91 (dd, J=13.5, 10.4 Hz, 2H), 6.42 (d, J=16.0 Hz, 1H), 4.22 (q, J=7.1 Hz, 2H), 2.58 (d, J=7.2 Hz, 4H), 2.30 (s, 3H), 1.71 (dt, J=13.5, 6.8 Hz, 2H), 1.31 (t, J=7.1 Hz, 3H), 0.87 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 470.31 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.28 (s, 1H), 9.33 (s, 1H), 8.05 (d, J=15.7 Hz, 3H), 7.49 (d, J=15.8 Hz, 1H), 7.30 (d, J=8.3 Hz, 2H), 7.20 (s, 1H), 7.05 (s, 1H), 6.34-6.26 (m, 1H), 2.81 (d, J=6.3 Hz, 4H), 1.77-1.65 (m, 2H), 0.83 (d, J=6.1 Hz, 12H). MS(ESI), m/z (%): 446.23 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.30 (s, 1H), 9.22 (s, 1H), 8.06 (s, 1H), 8.01 (s, 11H), 7.88 (t, J=8.5 Hz, 1H), 7.47 (d, J=15.8 Hz, 1H), 7.28 (d, J=9.6 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 7.07 (d, J=12.2 Hz, 1H), 6.95 (d, J=8.0 Hz, 1H), 6.30 (d, J=15.9 Hz, 1H), 2.80 (d, J=6.9 Hz, 4H), 2.27 (s, 3H), 1.71 (dt, J=13.3, 6.7 Hz, 2H), 0.82 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 442.25 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 8.81 (s, 1H), 8.24 (s, 1H), 7.73 (s, 1H), 7.66 (s, 1H), 7.59 (s, 1H), 7.56 (s, 1H), 7.51 (s, 11H), 7.26 (d, J=2.1 Hz, 1H), 7.24 (s, 1H), 5.97 (s, 1H), 3.91 (s, 2H), 2.61 (d, J=7.1 Hz, 4H), 2.44 (s, 3H), 1.60 (dd, J=13.4, 6.7 Hz, 2H), 1.46 (s, 9H), 0.77 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 547.38 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 8.77 (s, 1H), 8.24 (s, 1H), 7.73 (d, J=1.5 Hz, 1H), 7.66 (s, 2H), 7.51 (d, J=2.7 Hz, 1H), 7.42 (s, 2H), 5.95 (s, 1H), 3.89 (s, 2H), 2.60 (d, J=7.1 Hz, 4H), 2.44 (s, 3H), 1.59 (dd, J=13.3, 6.6 Hz, 2H), 1.46 (s, 9H), 0.76 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 547.38 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.04 (s, 1H), 8.73 (s, 1H), 8.27 (s, 1H), 7.44 (s, 1H), 7.38 (s, 1H), 7.36 (s, 1H), 7.27 (d, J=1.9 Hz, 1H), 7.25 (s, 1H), 6.04 (s, 1H), 3.79 (s, 2H), 2.61 (d, J=7.1 Hz, 4H), 2.45 (s, 3H), 1.60 (dd, J=12.4, 5.8 Hz, 2H), 0.77 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 457.26 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.06 (s, 1H), 8.73 (s, 1H), 8.33 (s, 1H), 7.64 (s, 1H), 7.52 (d, J=8.5 Hz, 1H), 7.46 (s, 1H), 7.28 (s, 2H), 6.04 (s, 1H), 3.92 (s, 2H), 2.64 (d, J=7.1 Hz, 4H), 2.45 (s, 3H), 1.64-1.61 (m, 2H), 0.81 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 491.22 [M+H]⁺. White solid.

¹H-NMR (600 MHz, DMSO-d₆) δ 12.02 (s, 1H), 8.80 (s, 1H), 8.23 (s, 1H), 7.73 (d, J=3.1 Hz, 1H), 7.68-7.66 (m, 1H), 7.27 (d, J=2.0 Hz, 1H), 7.25 (s, 1H), 7.21 (d, J=8.3 Hz, 1H), 6.93 (d, J=6.7 Hz, 1H), 6.04 (s, 1H), 3.90 (s, 2H), 2.62 (d, J=7.0 Hz, 4H), 2.45 (s, 3H), 1.59 (d, J=4.2 Hz, 2H), 0.76 (d, J=6.6 Hz, 12H). MS(ESI), m/z (%): 491.21 [M+H]⁺. White solid.

Test Method and Results of Inhibition Rate of IDO1 Enzyme in Hela Cells:

Human cervical cancer cell line Hela (obtained from Chinese academy of sciences cell bank) was cultured in logarithmic growth phase and counted after routine digestion. RPMI 1640 complete medium (Corning, USA, containing 10% FBS) was used to adjust the concentration to Ix 10′/ml, inoculated into 96-well plates, 100 ul/well, incubated for 24 hours.

Stimulant solution configuration: Human recombinant IFN-γ(Shanghai Sangon Biotech) was subpacked according to the instructions, the concentration was adjusted twice as high as the final concentration by RPMI1640 complete medium, that is 100 ng/ml.

Compounds solution configuration: DMSO was used to dissolve the drug, and then RPMI 1640 was used to dilute the drug to twice the detection concentration.

The old culture medium were discarded from 96-well plates, and added 100 ul stimulation solution and 100 ul compounds solution to each hole; set up interferon growth control group, each group had three multiple holes; incubated 48 hours.

180 uL medium from 96-well plate were collected and mixed with 45 μL of 30% (W/V) trichloroacetic acid. Plate was centrifuged for 5 min at 8000 rpm. The supernatant was added with fresh 4-dimethylaminobenzaldehyde (2%, W/V). After full shock, measured at 480 nm using a ElISA reader.

TABLE 7 Inhibition rate of compounds on IDO1 activity enzyme in Hela cells Inhibition rate (%) Compound Number 10 μmol 100 nmol Compound 9 100 100 Compound 13 100 100 Compound 14 100 100 Compound 396 100 69.2 Compound 397 100 75.5 Compound 403 100 76.4 Compound 404 100 73.2 Compound 518 100 76.8 Compound 525 100 75.1 Compound 564 100 72.2 Compound 772 100 74.2 Compound 779 100 77.1 Compound 1021 100 42.1 Compound 1022 53.7 21.2 Compound 1023 100 35.1 Compound 1024 58.2 29.5 Compound 1025 68.8 24.6 Compound 1026 54.3 21.0 Compound 1027 100 71.1 Compound 1028 100 41.5 Compound 1030 100 23.8 Compound 1031 72.7 29.6

The compounds described in the above table have certain inhibitory effects, Compounds 9, 13 and 14 can inhibit IDO-1 activity 100% at 100 nmol concentration.

TABLE 8 IC₅₀ Value (nmol/L) of compounds on IDO1 enzyme activity in Hela cells Inhibition rate IC₅₀ Compound Number (nmol/L) Compound 13 3.69 Compound 14 0.18 Compound 51 3.69 Compound 55 0.09 Compound 56 0.13 Compound 525 1.36 Compound 530 8.26 INCB024360 3.78 IN-4 1.56

As shown in the table above, the IC₅₀ of the compounds is lower than 100 nmol/L, and the activities of the compounds 525, 13, 14, 56, 55 and 51 can reach or exceed those of the positive control drugs INCB024360 and IN-4, indicating that these compounds have good IDO1 enzyme inhibitory activities.

As shown in Table 7 and Table 8 above, these compounds have potential therapeutic effects on colorectal cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, renal cancer, head and neck cancer, lymphoma, leukemia or melanoma with high expression of IDO1. It has potential therapeutic effects on other diseases such as viral infection, depression, organ transplant rejection or autoimmunity caused by high expression of IDO1.

INCB024360 control sample was purchased from Beijing Innochem Technology Co., Ltd. with batch number WG0292821-160526001. IN-4 was purchased from Medchem Express Biotechnology Company, USA, with batch number Lot #19346.

Pharmacokinetic Test and Results of Compound 55:

12 Male Sprague-Dawley rats were grouped random. The final concentration of compound 55 was 1.5 mg/ml. The drug was dissolved in a solvent system of 10% DMSO, 10% hydrogenated castor oil and 90% normal saline (compounds were dissolved by DMSO, hydrogenated castor oil and saline in turn by vortex or ultrasound), and the drug solution was given orally (30 mg/kg). The rats were fasted overnight but had free access to water, feeding resumed 4 hours after administration. Blood samples (0.3-0.4 mL) were collected into heparinized tubes by Retinal vein plexus at 0, 0.17, 0.33, 0.67, 1, 2, 4, 7, 10 and 24 hours after administration orally. Tubes were anticoagulated with heparin sodium (5% heparin sodium solution filled EP tube, poured out, dried). 100 uL plasma was obtained by centrifugation (10000 rpm, 3 min) and stored at −20° C. before analysis.

TABLE 9 Oral pharmacokinetic data of compound 55 Testing Compound Unit Compound 55 Dosage mg/kg 30 mg/kg AUC ng · h/mL 43655.98 T1/2 h 5.0 Cmax ng/mL 16760.13

The results showed that compound 55 had good pharmacokinetic parameters.

Pharmacodynamics of Some Compounds In Vivo (Intraperitoneal Injection):

The anti-colon cancer CT26 activity of these compounds was tested in vivo. 1×10⁶ CT26 cells were inoculated subcutaneously in the right axillary of BALB/c mice by cell suspension inoculation. When the growth of tumors were clearly observed, 42 moderately tumor size animals were selected and randomly divided into test group, solvent control group and positive drug group, with 6 animals in each group. The positive drug group was given 1-methyl-D-tryptophan 300 mg/kg daily by oral, and the INCB024360 group was given compound INCB024360 50 mg/kg daily by intraperitoneal injection. The compound groups were intraperitoneally injected with 50 mg/kg of the compound every day, while the solvent control group was given the same dosage with the same volume of mixed solvent. The weight of the mice and the length and short diameter of the transplanted tumors were measured three times a week during the administration. The tumor volume (VT), relative volume (RVT) and tumor proliferation rate (T/C %) were calculated. After two weeks of administration, nude mice bearing tumors in each experimental group were executed by neck-lifting method. Solid tumour tissues were completely dissected. The weight of tumors in each experimental group was measured and the growth inhibition rate (%) was calculated.

TABLE 10 Statistical table of tumor weight and inhibition rate of tumor weight Number of Tumor Inhibition animals weight rate Group (n) (mg) (%) Vehicle 6 3368.00 ± 557.96 0.0 1-MT 6 2509.17 ± 352.16 25.5 INCB024360 6 3026.17 ± 409.75 10.23 Compound 14 6 2727.33 ± 404.42 19.02 Compound 55 6 2121.17 ± 343.15 37.02

At the end of the experiment, the I-MT activity of the positive drug was better than that of INCB024360, and compound 55 was equivalent to that of 1-MT, which was better than that of INCB024360.

Pharmacodynamic of Some Compounds In Vivo (Oral Administration):

The anti-colon cancer CT26 activity of these compounds was tested in vivo. 1×10⁶ CT26 cells were inoculated subcutaneously in the right axillary of BALB/c mice by cell suspension inoculation. When the growth of tumors were clearly observed, 56 moderately tumor size animals were selected and randomly divided into test group, solvent control group and positive drug group, with 8 animals in each group. In the positive drug group, INCB024360 was given 50 mg/kg each time, compound 14 was given 50 mg/kg each time, compound 55 low dose group, compound 55 middle dose group and compound 55 high dose group were given 20 mg/kg, 50 mg/kg and 100 mg/kg respectively, compound 55 intraperitoneal injection group was given 50 mg/kg each time. The solvent control group was given the same volume of mixed solvents by oral. The above groups were administered twice a day. The weight of the mice and the length and short diameter of the transplanted tumors were measured three times a week during the administration. The tumor volume (VT), relative volume (RVT) and tumor proliferation rate (T/C %) were calculated. After two weeks of administration, nude mice bearing tumors in each experimental group were executed by neck-lifting method. Solid tumour tissues were completely dissected. The weight of tumors in each experimental group was measured and the growth inhibition rate (%) was calculated.

TABLE 11 Statistical table of tumor weight and inhibition rate of tumor weight Number of Tumor Inhibition Dose animals weight rate Group (mg/kg) (n) (mg) (%) Solvent control — 8 1267.13 ± 331.64  INCB024360 50 8 840.63 ± 144.34 33.66 Compound 55 20 8 1109.75 ± 191.47  12.42 Compound 55 50 8 924.25 ± 150.35 27.06 Compound 55 100 8 847.00 ± 305.01 33.16 Compound 14 50 8 793.38 ± 246.34 37.39 Compound 55 (IP) 50 8 824.00 ± 161.64 34.97

At the end of the experiment, the activity of compound 55, high dose group and compound 14 was similar to that of positive drug INCB024360.

Combining with the previous intraperitoneal injection in vivo pharmacodynamics experiments, compound 55 has better pharmacodynamics than INCB024360 under the condition of single administration per day, and is equivalent to INCB024360 under the condition of twice administration per day. The T1/2 data of INCB024360 reported in the literature were 2.3 hours and that of compound 55 was 5.0 hours. Combining animal pharmacodynamics experiment and pharmacokinetics experiment data, compound 55 has better pharmacokinetic properties than INCB024360, and can achieve considerable pharmacodynamics with fewer times of administration. 

1. A vinylarene derivative, which is characterized in that the vinylarene derivative is a compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof:

wherein W is selected from CH₂, O or NH; X is selected from CH₂, O or NH; Y is selected from O or S; J is selected from N or C; K is selected from N or C; M is selected from N or C; R¹ and R² are selected from H, COOH, CONHR¹⁰, —CONHSO₂R¹⁰, COOR¹⁰, C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl; R³ is selected from H, C₁-C₁₂ alkyl, halo C₁-C₁₂ alkyl, C₂-C₂ alkenyl, halo C₂-C₁₂ alkenyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl; R⁴ is selected from H or halogen; R⁵ is selected from H or halogen; R⁶ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ heterocycloalkyl, halo C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, halo C₁-C₁₂ alkoxy, C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, halo C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₃-C₁₂ cycloalkenyl, halo C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, halo C₂-C₁₂ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₁₂ alkyl, heteroaryl C₁-C₁₂ alkyl, aryl C₁-C₁₂ alkoxy, heteroaryl C₁-C₁₂ alkoxy, aryloxy or heteroaryloxy; R⁷ and R⁸ are the same or different and selected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ heterocycloalkyl, halo C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, halo C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₃-C₁₂ cycloalkenyl, halo C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, halo C₂-C₁₂ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₁₂ alkyl, heteroaryl C₁-C₁₂ alkyl; R⁹ is selected from the group consisting of H, C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, C₃-C₁₂ heterocycloalkyl, halo C₁-C₁₂ alkyl, C₁-C₁₂ alkoxy, halo C₁-C₁₂ alkoxy, C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, halo C₁-C₁₂ alkoxy C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, C₃-C₁₂ cycloalkenyl, halo C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, halo C₂-C₁₂ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₁₂ alkyl, heteroaryl C₁-C₁₂ alkyl; R¹⁰ is selected from the group consisting of C₁-C₁₂ alkyl, C₃-C₁₂ cycloalkyl, halo C₁-C₁₂ alkyl, halo C₃-C₁₂ cycloalkyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₁₂ alkyl, heteroaryl C₁-C₁₂ alkyl; R¹¹ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₁₀ alkyl, halo C₁-C₁₀ alkyl, C₁-C₁₀ alkoxy, halo C₁-C₁₀ alkoxy, C₁-C₁₀ alkylthiol, C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkoxycarbonyl, C₂-C₁₀ alkenyl, halo C₂-C₁₀ alkenyl, C₃-C₁₀ alkenyloxy, halo C₃-C₁₀ alkenyloxy, C₂-C₁₀ alkynyl, halo C₂-C₁₀ alkynyl, C₃-C₁₀ alkynyloxy, halo C₃-C₁₀ alkynyloxy, halo C₁-C₁₀ alkylthiol, halo C₁-C₁₀ alkylcarbonyl, C₁-C₁₀ alkylamino, halo C₁-C₁₀ alkylamino, C₂-C₁₀ dialkylamino, C₁-C₁₀ alkylcarbonylamino, halo C₁-C₁₀ alkylcarbonylamino, C₁-C₁₀ alkylaminocarbonyl or halo C₁-C₁₀ alkylaminocarbonyl.
 2. The vinylarene derivative of claim 1 is characterized by: the compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, as shown in formula I:

W is selected from CH₂, O or NH; X is selected from CH₂, O or NH; Y is selected from O or S; J is selected from N or C; K is selected from N or C; M is selected from N or C; R¹ and R² are selected from the group consisting of COOH, CONHR¹⁰, —CONHSO₂R¹⁰, COOR¹⁰, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl; R³ is selected from the group consisting of H, C₁-C₆ alkyl, halo C₁-C₆ alkyl, C₂-C₆ alkenyl, halo C₂-C₆ alkenyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl; R⁴ is selected from H or halogen; R⁵ is selected from H or halogen; R⁶ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₆ alkyl, heteroaryl C₁-C₆ alkyl, aryl C₁-C₆ alkoxy, heteroaryl C₁-C₆ alkoxy, aryloxy or heteroaryloxy; R⁷ and R⁸ are the same or different and selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₆ alkyl, heteroaryl C₁-C₆ alkyl; R⁹ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl; R¹⁰ is selected from the group consisting of C₁-C₆ alkyl, C₃-C₆ cycloalkyl, halo C₁-C₆ alkyl, halo C₃-C₆ cycloalkyl, unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₆ alkyl, heteroaryl C₁-C₆ alkyl; R¹¹ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₆ alkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkylthiol, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₂-C₆ alkenyl, halo C₂-C₆ alkenyl, C₃-C₆ alkenyloxy, halo C₃-C₆ alkenyloxy, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, C₃-C₆ alkynyloxy, halo C₃-C₆ alkynyloxy, halo C₁-C₆ alkylthiol, halo C₁-C₆ alkylcarbonyl, C₁-C₆ alkylamino, halo C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₁-C₆ alkylcarbonylamino, halo C₁-C₆ alkylcarbonylamino, C₁-C₆ alkylaminocarbonyl or halo C₁-C₆ alkylaminocarbonyl.
 3. The vinylarene derivative of claim 2 is characterized by: the compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, as shown in formula I:

W is selected from NH; X is selected from CH₂, O or NH; Y is selected from O or S; R¹ and R² are selected from COOH, CONHR¹⁰, —CONHSO₂R¹⁰, COOR¹⁰,

R³ is selected from the group consisting of H, C₁-C₂ alkyl, halo C₁-C₂ alkyl, C₂-C₄ alkenyl, halo C₂-C₄ alkenyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: phenyl, pyridyl; R⁴ is selected from H or halogen; R⁵ is selected from H or halogen; R⁶ is selected from the group consisting of H, halogen, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₆ alkyl, heteroaryl C₁-C₃ alkyl, aryl C₁-C₃ alkoxy, heteroaryl C₁-C₃ alkoxy, aryloxy or heteroaryloxy; R⁷ and R⁸ are the same or different and selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, C₂-C₆ alkynyl, the following groups which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₃ alkyl, heteroaryl C₁-C₃ alkyl; R⁹ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₃ alkyl, heteroaryl C₁-C₃ alkyl; R¹⁰ is selected from the group consisting of C₁-C₃ alkyl, C₃-C₆ cycloalkyl, halo C₁-C₃ alkyl, halo C₃-C₆ cycloalkyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₃ alkyl, heteroaryl C₁-C₃ alkyl; R¹¹ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₆ alkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkylthiol, C₁-C₆ alkylcarbonyl, C₁-C₆ alkoxycarbonyl, C₂-C₆ alkenyl, halo C₂-C₆ alkenyl, C₃-C₆ alkenyloxy, halo C₃-C₆ alkenyloxy, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, C₃-C₆ alkynyloxy, halo C₃-C₆ alkynyloxy, halo C₁-C₆ alkylthiol, halo C₁-C₆ alkylcarbonyl, C₁-C₆ alkylamino, halo C₁-C₆ alkylamino, C₂-C₆ dialkylamino, C₁-C₆ alkylcarbonylamino, halo C₁-C₆ alkylcarbonylamino, C₁-C₆ alkylaminocarbonyl or halo C₁-C₆ alkylaminocarbonyl.
 4. The vinylarene derivative of claim 3 is characterized by: the compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, as shown in formula I:

W is selected from NH; X is selected from CH₂, O or NH; Y is selected from O or S; R¹ and R² are selected from COOH,

 CONHSO₂CH₃, CONHSO₂CF₃ or COOCH₂CH₃: R³ is selected from H, CH₃, CH₂CH₃ or CF₃; R⁴ is selected from H; R⁵ is selected from H; R⁶ is selected from H; R⁷ and R⁸ are the same or different and selected from the group consisting of H, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl; R⁹ is selected from the group consisting of H, C₁-C₆ alkyl, C₃-C₆ cycloalkyl, C₃-C₆ heterocycloalkyl, halo C₁-C₆ alkyl, C₁-C₆ alkoxy, halo C₁-C₆ alkoxy, C₁-C₆ alkoxy C₁-C₆ alkyl, halo C₁-C₆ alkoxy C₁-C₆ alkyl, C₂-C₆ alkenyl, C₃-C₆ cycloalkenyl, halo C₂-C₆ alkenyl, C₂-C₆ alkynyl, halo C₂-C₆ alkynyl, the following group which is unsubstituted or substituted by 1-5 R¹¹: aryl, heteroaryl, aryl C₁-C₃ alkyl, heteroaryl C₂-C₃ alkyl; R¹¹ is selected from the group consisting of H, halogen, nitro, cyano, C₁-C₃ alkyl, halo C₁-C₃ alkyl, C₁-C₃ alkoxy, halo C₁-C₃ alkoxy, C₁-C₃ alkylthiol, C₁-C₃ alkylcarbonyl, C₁-C₃ alkoxycarbonyl, C₂-C₃ alkenyl, halo C₂-C₃ alkenyl, C₃-C₆ alkenyloxy, halo C₃-C₆ alkenyloxy, C₂-C₃ alkynyl, halo C₂-C₃ alkynyl, C₃-C₆ alkynyloxy, halo C₃-C₆ alkynyloxy, halo C₁-C₃ alkylthiol, halo C₁-C₃ alkylcarbonyl, C₁-C₃ alkylamino, halo C₁-C₃ alkylamino, C₂-C₃ dialkylamino, C₁-C₃ alkylcarbonylamino, halo C₁-C₃ alkylcarbonylamino, C₁-C₃ alkylaminocarbonyl or halo C₁-C₃ alkylaminocarbonyl.
 5. The vinylarene derivative of claim 4 is characterized by: the compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, as shown in formula I:

W is NH; X is NH or CH₂; Y is O; R¹ and R² is selected from COOH,

 or COOCH₂CH₃: R³ is selected from CH₃; R⁴ is selected from H; R⁵ is selected from H; R⁶ is selected from H; R⁷ and R⁸ are the same or different and selected from n-butyl or isobutyl; R⁹ is selected from the group consisting of 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2,4-dimethylphenyl, 2,4-difluorophenyl, 2-fluoro-4-methylphenyl, 3-trifluoromethyl-4-chlorophenyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 2,4-dichlorophenyl, 2-fluorophenyl, 4-fluorophenyl, 3-fluorophenyl or 5-methylisoxazolyl.
 6. The application of a vinylarene derivative described in claim 1 is characterized by: the compound shown in formula I, its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, or a combination thereof, in the preparation of inhibitors of IDO-1 enzyme activity.
 7. The application of a vinylarene derivative described in claim 1 is characterized by: its stereoisomer, cis-trans isomer, tautomer and pharmaceutically acceptable salt thereof, or a combination thereof, in the preparation of an anti-cancer drug, a viral infectious agent, a depressant, an organ transplant rejection agent or an autoimmune enhancer.
 8. The application of a vinylarene derivative of claim 7 is characterized by: the cancer is colon cancer, pancreatic cancer, breast cancer, prostate cancer, lung cancer, ovarian cancer, cervical cancer, kidney cancer, head and neck cancer, lymphoma, leukemia or melanoma.
 9. A pharmaceutical composition comprising any one or more compounds in claim 1, its stereoisomer, cis-trans isomer, tautomer, pharmaceutically acceptable salt thereof and pharmaceutically acceptable carriers or diluents. 